Livro de Resumos by Diana Pinto

13th National Organic Chemistry Meeting 6th National Medicinal Chemistry Meeting

15th - 17th January 2020, Aveiro, Portugal

Book of Abstracts

Welcome Dear Colleagues, The Divisions of Organic Chemistry and Medicinal Chemistry of the Portuguese Chemical Society (SPQ) are organizing, in a single event, the 13th National Organic Chemistry Meeting (13ENQO) and the 6th National Medicinal Chemistry Meeting (6ENQT) that will take place on January 15-17, 2020 at the University of Aveiro, Portugal. We warmly invite you to attend this scientific meeting. The interdisciplinary nature of the meeting represents a unique opportunity to bring together specialists from all domains of the Organic and Medicinal Chemistry areas, providing a forum to discuss recent developments and innovative ideas and foster new collaborations. An attractive program is being prepared, spanning advances in both established fields and emerging topics. The meeting comprises plenary and keynote lectures from renowned national and international scientists, invited

oral

communications,

selected

oral

communications,

and

poster

communications that will surely attract the interest of a vast audience. The attendance of students and young researchers is strongly encouraged and supported by affordable registration fees. Aveiro is a booming and beautiful city in the North of Portugal, located on the shore of the Atlantic Ocean. It is known as â&#x20AC;&#x153;the Portuguese Veniceâ&#x20AC;? due to its distinctive lagoon and system of canals. The city is easily reached by train from Porto or Lisbon international airports. We look forward to welcoming you in Aveiro in January 2020 Augusto C. TomĂŠ & M. Matilde Marques Conference Chairpersons

Committees Scientific Committee Anthony Burke (UÉvora) Artur Silva - President of the Portuguese Chemical Society Augusto Tomé - Chairperson & President of the Organic Chemistry Division Carlos Afonso (FFUL) Emília Sousa (FFUP) – Executive Committee, Medicinal Chemistry Division Jorge Salvador (FFUC) Maria Lurdes Cristiano (UAlgarve) Maria Manuela Raposo (DQUM) Maria Manuel Marques (FCTUNL) Maria Santos (FFUL) – Executive Committee, Medicinal Chemistry Division M. Matilde Marques - Chairperson & President of the Medicinal Chemistry Division Mariette Pereira (DQUC) Patrício Soares da Silva (BIAL) Paula Branco (FCTUNL) – Vice-President of the Organic Chemistry Division Paula Castilho (UMadeira) Paula Gomes (FCUP) – Executive Committee, Medicinal Chemistry Division Rui Loureiro (Hovione) Rui Moreira (FFUL) Teresa Pinho e Melo (DQUC) – Vice-President of the Organic Chemistry Division Victor Freitas (FCUP)

Organizing Committee Augusto Tomé - Chairperson & President of the Organic Chemistry Division M. Matilde Marques - Chairperson & President of the Medicinal Chemistry Division Diana Pinto (DQUA) Emília Sousa (FFUP) – Executive Committee, Medicinal Chemistry Division Graça Rocha (DQUA) Maria da Graça Neves (DQUA) Maria do Amparo Faustino (DQUA) Maria Santos (FFUL) – Executive Committee, Medicinal Chemistry Division Mário Simões (DQUA) Paula Branco (FCTUNL) – Vice-President of the Organic Chemistry Division Paula Gomes (FCUP) – Executive Committee, Medicinal Chemistry Division Samuel Guieu (DQUA) Teresa Pinho e Melo (DQUC) – Vice-President of the Organic Chemistry Division Vera Silva (DQUA)

Secretary Leonardo Mendes (SPQ) Cristina Campos (SPQ) Sociedade Portuguesa de Química Av. República nº 45, 3º Esq., 1050-187 Lisboa, Portugal

Acknowledgments and Sponsors

General Information Venue: The meeting will be held at the Rectory building, University of Aveiro.

Meeting Language: The meeting’s official language will be English. All lectures and discussions in sessions will be conducted in English. Welcome Reception: The Welcome Reception will be held at the University Restaurant (building F. Conference Dinner: The Conference Dinner will be held at the University Restaurant (building F).

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Speakers are kindly asked to contact the organizing committee at the reception desk to deliver the PowerPoint presentation in a pen drive before session start.

•

Posters will be displayed in building 24 (close to the Rectory). Two poster sessions are scheduled: 15th and 16th January, from 16:30 h to 17:30 h. Authors are requested to display their own posters on the boards before the corresponding session. The posters should be removed by the end of the day. Authors are requested to stay near their posters during the poster session in order to be able to answer any questions asked by the participants.

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The organizers will provide materials necessary to affix posters on the boards.

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The authors are requested to stay near their posters during the poster session to be able to answer any questions asked by the participants.

UA Campus

Awards of the Organic Chemistry Division 2019 •

Portuguese Award for Best Young Organic Chemist 2019 This prize is sponsored by the European Journal of Organic Chemistry and ChemPubSoc Europe, and aims to promote excellence in organic chemistry developed by young researchers in national institutions. The

award is intended for PhD researchers under 40 years of age at the start of the National Organic Chemistry Meeting, and is assigned based on the quality and core research impact in the area of Organic Chemistry conducted in national institutions.

•

Portuguese Award for Best PhD Thesis in Organic Chemistry 2019

This prize seeks to recognize the scientific merit of doctorates carried out mainly in national institutions. The award is intended for recent PhD graduates, who obtained the degree in national institutions, and is assigned based on the work developed during the PhD conducted in the area of Organic Chemistry.

•

Portuguese Award for Best Master Thesis in Organic Chemistry 2019

This prize seeks to recognize the scientific merit of Masters studies performed mostly in national institutions. The award is intended for recent masters graduates, who obtained the degree in national institutions, and is assigned based on the work performed during the Masters in the field of Organic Chemistry.

•

Award for best oral communication in Organic Chemistry

This prize seeks to recognize the best oral communication in Organic Chemistry.

•

Award for best poster in Organic Chemistry

This prize seeks to recognize the best poster in Organic Chemistry.

Awards of the Medicinal Chemistry Division 2019 •

Portuguese Award for Best PhD Thesis in Medicinal Chemistry 2019

Portuguese Award for Best Master Thesis in Medicinal Chemistry 2019

•

Award for best oral communication in Medicinal Chemistry

This prize seeks to recognize the best oral communication in Medicinal Chemistry.

•

Award for best poster in Medicinal Chemistry

This prize seeks to recognize the best poster in Medicinal Chemistry.

Index Scientific Program

List of Communications Plenary Lectures

Keynote Lectures

Invited Oral Communications

Portuguese Award for Best Young Organic Chemist 2019

Oral Communications

Poster Communications

Abstracts Plenary Lectures

Keynote Lectures

Invited Oral Communications

Portuguese Award for Best Young Organic Chemist 2019

Oral Communications

Poster Communications

Catalysis

Computational methods and drug design

Green chemistry

Materials chemistry

Natural product chemistry

103

Pharmacokinetics and drug metabolism

112

Physical organic chemistry

115

Quantitative structure-activity relationships

118

Novel biologically active compounds

119

Synthesis

146

Author index

172

List of participants

182

Edifício da Reitoria

SCIENTIFIC PROGRAM

Scientific Program Contributions on the following topics were received: •

Catalysis

•

Computational methods and drug design

•

Green chemistry

•

Materials chemistry

•

Natural product chemistry

•

Novel biologically active compounds

•

Pharmacokinetics and drug metabolism

•

Physical organic chemistry

•

Quantitative structure-activity relationships

•

Synthesis

The Meeting schedules 6 Plenary lectures, 7 Keynote addresses, 6 Invited Oral communications, 31 Oral communications and 2 Poster sessions.

Program Morning Sessions

Afternoon Sessions

Detailed Program Wednesday, the 15th of January 2020 9:00-9:45 9:45-10:15

Registration Opening Ceremony

Session 1 Chaired by: M. Graça Neves and Maria Manuel B. Marques 10:15-11:00

PL1 - Subphthalocyanines: singular aromatic non-planar molecules Tomás Torres Department of Organic Chemistry, Autonoma University of Madrid, Madrid, Spain

11:00-11:30

Coffee Break

11:30-12:00

KN1 - From one target to multi-target drugs: when pharmacological promiscuity becomes an advantage Fernanda Borges CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto

12:00-12:15

IOC1 - Heterocyclic probes: design, synthesis and application in chemosensing and molecular bioimaging Susana P. G. Costa Centre of Chemistry, University of Minho, Campus de Gualtar, Braga, Portugal

12:15-12:30

OC1 - Fast color switching materials using photochromic fused-naphthopyrans P. Coelho Chemistry Center - Vila Real, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal

12:30-12:45

OC2 - Lead to target: a computational approach to identify the protein targets of molecules with known experimental biological activity Sérgio F. Sousa UCIBIO/REQUIMTE – BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal

12:45-13:00

OC3 - Small organic fluorophores. Structure–property correlation of solid emissive compounds Patricia A. A. M. Vaz LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal

13:00-14:30

14:30-15:15

Lunch Session 2 Chaired by: Paula Branco and Jorge Salvador PL2 - Sugar chemistry unveiling the secrets of nature Amélia Rauter Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal

15:15-15:30

IOC2 - 5-Substituted (thio)barbiturates as proteasome inhibitors for cancer therapy: design, synthesis and biological evaluation Samuel Silvestre CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal

15:30-15:45

OC4 - On the use of molecular interaction fields to predict drug-resistance Ana I. Mata CQC and Department of Chemistry, University of Coimbra, Coimbra, Portugal

15:45-16:00

OC5 - Heterogeneous catalysts for biodiesel production: microwave versus conventional assisted method Graça Rocha University of Aveiro, Aveiro, Portugal

16:00-16:15

16:15-16:30

OC6 - Abietane diterpenoids from Plectranthus spp.: a source of lead molecules Patrícia Rijo CBIOS-Center for Research in Biosciences & Health Technologies, Universidade Lusófona de Humanidades e Tecnologias, Lisboa, Portugal

OC7 - Tetrapyrrole-based catalysts for oxidative transformations through sustainable processes M. J. F. Calvete CQC, Department of Chemistry, University of Coimbra, Coimbra, Portugal

16:30-17:30 17:30-18:00

Coffee Break and Poster Session 1 (PC1 – PC45) KN2 - Synthetic transformations under flow conditions Carlos A. M. Afonso Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal

18:00-18:15

OC8 - Novel antiproliferative N-dodecyl glucuronamide-based nucleosides inducing apoptosis in chronic myeloid leukemia cells Nuno M. Xavier Centro de Quimica e Bioquimica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal

18:15-18:30

OC9 - Exploring halogen-free aminopyridines as suitable scaffolds for direct access to azaindoles A. Sofia Santos LAQV-Requimte and Department of Chemistry, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal

18:30-18:45

OC10 - Epigenetic drug discovery: design, synthesis and biological evaluation of novel EZH2 inhibitors against cancer Filipa Ramilo-Gomes Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal

18:45-19:00

OC11 - Exploring heterocyclic frameworks – small molecules, endless potential Carolina S. Marques Centro de Química de Évora (CQE & LAQV-REQUIMTE), University of Évora, Institute for Research and Advanced Studies, Évora, Portugal

19:00-20:30

Welcome Reception

Thursday, the 16th of January 2020 Session 3 Chaired by : Mariette Pereira and Rui Moreira 9:00-9:45

PL3 - Development of tools and drugs for membrane proteins involved in inflammation, immunity and cancer Christa E. Müller Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany

9:45-10:15

KN3 - Halophytes from the salt pans of Ria de Aveiro: gourmet products with nutritional health benefits Diana C. G. A. Pinto LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal

10:15-10:30

OC12 - N4,N9-disubstituted antimalarials

4,9-diaminoacridines

potential

multi-stage

Cátia Teixeira LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal

10:30-10:45

OC13 - Synthesis and structural modulation of tetrapyrrolic macrocycles: potential probes for PET and MRI imaging? Sara M. A. Pinto Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal

10:45-11:00

OC14 - Triggering the immune system to fight cancer – activation of NK cells with small organic molecules Pedro F. Pinheiro Centro de Química Estrutural – Instituto Superior Técnico, Lisboa, Portugal

11:00-11:30

Coffee Break

11:30-12:00

KN4 - Why going NANO on cancer healthcare? João Conde

12:00-12:15

IOC3 - Synthesis, photophysical properties and applications of pyrano-3deoxyanthocyanin dyes Luis Cruz

Instituto de Medicina Molecular (iMM), Faculdade de Medicina, Universidade de Lisboa Lisboa, Portugal

LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal

12:15-12:30

OC15 - S,N-peptide functionalisation with ortho activated aldehydes Hélio Faustino

12:30-12:45

OC16 - Fighting breast cancer with ruthenium-based metallodrugs endowed with tumor-targeting vectors Leonor Côrte-Real

Research Institute for Medicines (iMed.ULisboa). Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal

Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, Lisboa, Portugal

12:45-13:00 13:00-14:30

14:30-15:15

OC17 - Benzylaminobenziodoxolone – a new reagent for electrophilic amination Diogo L. Poeira LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, Caparica, Portugal

Lunch Session 4 Chaired by: Pedro Góis and Paula Gomes PL4 - From imidazoles to chromenes: a personal journey in organic synthesis M. Fernanda Proença CQ-UM and Department of Chemistry, University of Minho, Campus de Gualtar, Braga, Portugal

15:15-15:30

IOC4 - Harnessing the power of resin acids for innovative antimicrobial research Vânia M. Moreira Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Portugal

15:30-15:45

OC18 - Inhibition of pancreatic α-amylase activity by a group of hydroxyxanthones Clementina M. M. Santos Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Bragança, Portugal

15:45-16:00

OC19 - Multi-component synthesis of novel 1,2,3-triazole-dihydropyrimidinone hybrids: tackling cancer and Alzheimer’s disease Elisabete P. Carreiro Centro de Química de Évora & LAQV-Requimte, University of Évora, Institute for Research and Advanced Training (IIFA), Évora, Portugal

16:00-16:15

OC20 - iLiquids4Malaria: from ILs to SAILs – an insight Ricardo Ferraz

16:15-16:30

OC21 - Sustainable synthesis of biologically important furan derivatives Ana C. Fernandes

Ciências Químicas e das Biomoléculas, Escola Superior de Saúde, Instituto Politécnico do Porto, Porto, Portugal

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal

16:30-17:30 17:30-18:00

Coffee Break and Poster Session 2 (PC46 – PC90) KN5 - Challenges in the design of oncogene and p53 expression modulators Alexandra Paulo iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal

18:00-19:00 19:00-20:30

Meetings of the Organic Chemistry and Medicinal Chemistry Divisions Conference Dinner

Friday, the 17th of January 2020 Session 5 Chaired by: M. Lurdes Cristiano and Maria Santos 9:00-9:45

PL5 - Fluorine chemistry to diagnose and cure diseases Véronique Gouverneur University of Oxford, Chemistry Research Laboratory, Oxford, UK

9:45-10:15

KN6 - Opicapone, a long-acting anti-parkinsonian drug. From in silico simulations to in human trials. P. Nuno Alma Department of Research and Development, BIAL-Portela & Cª, S.A, Coronado (S. Mamede & S. Romão), Portugal

10:15-10:30

OC22 - Photodynamic inactivation of Escherichia coli using neutral and cationic porphyrins Sara R. D. Gamelas LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal

10:30-10:45

OC23 - Asymmetric Neber approach to chiral 2-(tetrazol-5-yl)-2H-azirines Cláudia C. Alves CQC and Department of Chemistry, University of Coimbra; Coimbra, Portugal

10:45-11:00

OC24 - A sustainable aproach for the discovery of medicinal relevant scaffolds: From furans to cyclopentenones Rafael F. A. Gomes Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal

11:00-11:30 11:30-12:00

Coffee Break KN7 - Heterocycles from nitrosoalkenes, azoalkenes and 1-azadienes Teresa M. V. D. Pinho e Melo CQC and Department of Chemistry, University of Coimbra, Coimbra, Portugal

12:00-12:15

IOC5 - Helping mother nature through medicinal chemistry in lato sensu: new nature-inspired antifouling compounds obtained by synthesis Marta Correia-da-Silva Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal

12:15-12:30

12:30-12:45

OC25 - Expeditious synthesis of chiral sulfones via umpolung reaction João Macara LAQV-REQUIMTE, Departamento de Química Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa Campus de Caparica, Caparica, Portugal

OC26 - Platinum(II) ring-fused chlorin photosensitizers for cancer theranostic applications: synthesis, in vitro cell biology and in vivo proof of concept Bruno F. O. Nascimento CQC and Department of Chemistry, University of Coimbra, Coimbra, Portugal

12:45-13:00

OC27 - A novel route to the synthesis of xanthones by carbonylative Suzuki coupling Daniela R. P. Loureiro Department of Chemical Sciences, Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal

13:00-14:30

14:30-15:15

Lunch Session 6 Chaired by: Victor Freitas and Emília Sousa PL6 - Activity-based glycosidase profiling in biomedicine and biotechnology Herman Overkleeft Leiden Institute of Chemistry, Leiden University, The Netherlands

15:15-15:30

IOC6 - Dihydropyrazolylquinolones and furoquinolines from quinolone-based chalcones as potential antioxidant and anticholinesterase agents Vera L. M. Silva LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal

15:30-15:45

15:45-16:00

OC28 - Active pharmaceutical ionic liquids as a new platform for tuberculosis L. C. Branco LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal

OC29 - Versatile phthalocyanine dyes as ‘therapeutic photoinactivation of microorganisms Leandro M. O. Lourenço

window’

LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, Aveiro, Portugal

for

16:00-16:15

OC30 - Chalcones modulate the production of reactive species and NETs release by human neutrophils in normal and hyperglycemic conditions Adelaide Sousa LAQV-REQUIMTE, Applied Chemistry Laboratory, Department of Chemical Sciences, Faculty of Pharmacy of the University of Porto, Porto, Portugal

16:15-16:30

OC31 - Rosamine fluorophores: Improvements on the Friedel–Crafts acylation using microwave and ohmic heating Ana M. G. Silva REQUIMTE-LAQV, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Porto, Portugal.

16:30-16:45 16:45-17:00 17:00-17:30

Awards OC/MC Divisions 2019 Award Best Young Org. Chem. – Nuno Moura (UA) Awards and Closing Ceremony

Complexo Pedagรณgico

LIST OF COMMUNICATIONS

Plenary Lectures PL1 PL2 PL3 PL4 PL5 PL6

Tomás Torres, “Subphthalocyanines: singular aromatic non-planar molecules” Amélia P. Rauter, “Sugar chemistry unveiling the secrets of nature” Christa E. Müller, “Development of tools and drugs for membrane proteins involved in inflammation, immunity and cancer” M. Fernanda Proença, “From imidazoles to chromenes: a personal journey in organic synthesis” Véronique Gouverneur, “Fluorine chemistry to diagnose and cure diseases” Herman Overkleeft, “Activity-based glycosidase profiling in biomedicine and biotechnology”

Keynote Lectures KN1 KN2 KN3 KN4 KN5 KN6 KN7

Fernanda Borges, “From one target to multi-target drugs: when pharmacological promiscuity becomes an advantage” Carlos A. M. Afonso, “Synthetic transformations under flow conditions” Diana C. G. A. Pinto, “Halophytes from the salt pans of Ria de Aveiro: gourmet products with nutritional health benefits” João Conde, “Why going NANO on cancer healthcare?” Alexandra Paulo, “Challenges in the design of oncogene and p53 expression modulators” P. Nuno Alma, “Opicapone, a long-acting anti-parkinsonian drug. From in silico simulations to in human trials” Teresa M. V. D. Pinho e Melo, “Heterocycles from nitrosoalkenes, azoalkenes and 1-azadienes”

Invited Oral Communications IOC1 IOC2 IOC3 IOC4 IOC5 IOC6

Susana P. G. Costa, “Heterocyclic probes: design, synthesis and application in chemosensing and molecular bioimaging” Samuel Silvestre, “5-Substituted (thio)barbiturates as proteasome inhibitors for cancer therapy: design, synthesis and biological evaluation” Luis Cruz, “Synthesis, photophysical properties and applications of pyrano-3deoxyanthocyanin dyes” Vânia M. Moreira, “Harnessing the power of resin acids for innovative antimicrobial research” Marta Correia-da-Silva, “Helping mother nature through medicinal chemistry in lato sensu: new nature-inspired antifouling compounds obtained by synthesis” Vera L. M. Silva, “Dihydropyrazolylquinolones and furoquinolines from quinolonebased chalcones as potential antioxidant and anticholinesterase agents”

Portuguese Award for Best Young Organic Chemist 2019 Nuno M. M. Moura, “The role of the formyl group on the β-modification of porphyrinic macrocycles”

Oral Communications OC1 OC2 OC3 OC4 OC5 OC6 OC7 OC8 OC9 OC10 OC11 OC12 OC13 OC14 OC15 OC16 OC17 OC18 OC19 OC20 OC21 OC22 OC23 OC24 OC25 OC26 OC27

P. Coelho, “Fast color switching materials using photochromic fusednaphthopyrans” Sérgio F. Sousa, “Lead to target: a computational approach to identify the protein targets of molecules with known experimental biological activity” Patrícia A. A. M. Vaz, “Small organic fluorophores. Structure–property correlation of solid emissive compounds” Ana I. Mata, “On the use of molecular interaction fields to predict drug-resistance” Graça Rocha, “Heterogeneous catalysts for biodiesel production: microwave versus conventional assisted method” Patrícia Rijo, “Abietane diterpenoids from Plectranthus spp.: a source of lead molecules” M. J. F. Calvete, “Tetrapyrrole-based catalysts for oxidative transformations through sustainable processes” Nuno M. Xavier, “Novel antiproliferative N-dodecyl glucuronamide-based nucleosides inducing apoptosis in chronic myeloid leukemia cells” A. Sofia Santos, “Exploring halogen-free aminopyridines as suitable scaffolds for direct access to azaindoles” Filipa Ramilo-Gomes, “Epigenetic drug discovery: design, synthesis and biological evaluation of novel EZH2 inhibitors against cancer” Carolina S. Marques, “Exploring heterocyclic frameworks – small molecules, endless potential” Cátia Teixeira, “N4,N9-disubstituted 4,9-diaminoacridines as potential multi-stage antimalarials” Sara M. A. Pinto, “Synthesis and structural modulation of tetrapyrrolic macrocycles: potential probes for PET and MRI imaging?” Pedro F. Pinheiro, “Triggering the immune system to fight cancer – activation of NK cells with small organic molecules” Hélio Faustino, “S,N-peptide functionalisation with ortho activated aldehydes” Leonor Côrte-Real, “Fighting breast cancer with ruthenium-based metallodrugs endowed with tumor-targeting vectors” Diogo L. Poeira, “Benzylaminobenziodoxolone – a new reagent for electrophilic amination” Clementina M. M. Santos, “Inhibition of pancreatic α-amylase activity by a group of hydroxyxanthones” Elisabete P. Carreiro, “Multi-component synthesis of novel 1,2,3-triazoledihydropyrimidinone hybrids: tackling cancer and Alzheimer’s disease” Ricardo Ferraz, “iLiquids4Malaria: from ILs to SAILs – an insight” Ana C. Fernandes, “Sustainable synthesis of biologically important furan derivatives” Sara R. D. Gamelas, “Photodynamic inactivation of Escherichia coli using neutral and cationic porphyrins” Cláudia C. Alves, “Asymmetric Neber approach to chiral 2-(tetrazol-5-yl)-2Hazirines” Rafael F. A. Gomes, “A sustainable aproach for the discovery of medicinal relevant scaffolds: from furans to cyclopentenones” João Macara, “Expeditious synthesis of chiral sulfones via umpolung reaction” Bruno F. O. Nascimento, “Platinum(II) ring-fused chlorin photosensitizers for cancer theranostic applications: synthesis, in vitro cell biology and in vivo proof of concept” Daniela R. P. Loureiro, “A novel route to the synthesis of xanthones by carbonylative Suzuki coupling”

OC28 L. C. Branco, “Active pharmaceutical ionic liquids as a new platform for tuberculosis” OC29 Leandro M. O. Lourenço, “Versatile phthalocyanine dyes as ‘therapeutic window’ for photoinactivation of microorganisms” OC30 Adelaide Sousa, “Chalcones modulate the production of reactive species and NETs release by human neutrophils in normal and hyperglycemic conditions” OC31 Ana M. G. Silva, “Rosamine fluorophores: improvements on the Friedel–Crafts acylation using microwave and ohmic heating”

Poster Communications Poster Session 1 PC1 PC2 PC3 PC4 PC5 PC6 PC7 PC8 PC9 PC10 PC11 PC12 PC13 PC14 PC15 PC16 PC17 PC18 PC19 PC20 PC21 PC22

Vasco F. Batista, “Monoamine oxidase: a versatile tool in amine resolution and functionalization” Mariette M. Pereira, “Catalytic sequential reactions in organic synthesis: novel strategies for multifunctionalization of olefins” Nélia C. T. Tavares, “Enantioselective alkynylation of aldehydes under mild and cheap conditions: ligand screening and optimization studies” João P. Luís, “Targeting neuroinflammation: a combined virtual screening protocol towards the discovery of interleukin-1 receptor type I (IL-1R1) modulators” Sara N. Garcia, “Development of hit molecules for hexokinase 2 inhibition: an attempt to target glycolysis and apoptosis in cancer cells” Judite R.M. Coimbra, “Application of computational methods for discovery of novel BACE1 inhibitors: ligand- and structure-based protocols with in vitro evaluation” José Miguel P. Ferreira de Oliveira, “Protocol refinement in tumour spheroid formation and machine-learning classification” Juliana G. Pereira, “A new method for aminal formation under mild conditions” Sónia Rocha, “Optimization of kinetic parameters to assess glycogen phosphorylase activity using a microanalysis method” Rima Tedjini, “One-pot mechanosynthesis and catalytic performance of tripodal metallic complexes” Carla Gomes, “Modern methods for the synthesis of metalloporphyrins” Declan C. Mullen, “Development of novel antimicrobial celluloses” Ana Júlio, “Ionic liquids as a strategy to improve drug delivery systems” M. Bernardo, “Synthesis of functional naphthalene diimides for photoactive materials” Luís Fontes, “Synthesis and photophysical characterization of triphenylpyridine fluorophores” Daniela Silva, “New co-crystals of ketoconazole” Joana F.B. Barata, “Photoactive systems based on corrole macrocycles and nanoparticles” Raquel V. Barrulas, “Displaying molecular interactions in ionic liquids through NMR” Luísa M. Ferreira, “Protein and alkaloids recover from lupine debittering leaching media” Nidia Maldonado-Carmona, “Acetylated lignin nanoparticles: a potential photosensitizer vehicle for antimicrobial photodynamic therapy” Maribel Teixeira, “Evaluation of growth inhibition effect of free and nanoincorporated xanthone derivative on a human breast cancer cell line” Marina Costa, “Chitosan hydrogel polymer bases with potential application in veterinary medicine”

PC23 PC24 PC25 PC26 PC27 PC28 PC29 PC30 PC31 PC32 PC33 PC34 PC35 PC36 PC37 PC38 PC39 PC40 PC41 PC42 PC43 PC44 PC45

Joana F. Leal, “Structure and toxicity of STX-group toxins” Mariana Lucas, “Evaluation of the antioxidant activity of curcumin and piperine extracts, and their combination, in in vitro cellular and non-cellular systems” Lídia A. S. Cavaca, “Biomass valorization: methanolysis of oleuropein” Marisa Freitas, “Flavonoids versus chalcones: which are the most efficient inhibitors of key digestive enzymes in the management of diabetes mellitus?” Carina Proença, “The promising effect of flavonoids in type 2 diabetes therapy: inhibition of key enzymatic targets with a significant role in the development of hyperglycaemia” Yonah Favero, “Application of hydralcoholic extracts of Salvia officinalis and Salvia elegans in cosmetic formulations” Carla T. P. Coelho, “Study of antagonistic interaction of extracts of Banisteriopsis laevifolia (A.Juss) B. Gates against Magnaporthe oryzae” Luciana B. Silva, “Valorization of sugars from the eucalypto wood liquefaction process” Daniela Ramírez, “Effect of gamma irradiation on physicochemical properties and antifunctional activity of essential oils of chilca (Baccharis latifolia) and muña (Minthostachys mollis)” Karyna Lysenko, “g-Cyclodextrin inclusion of efavirenz and its effect on aqueous solubility” Cátia F. Marques, “Montelukast metabolism: new insights into neurotoxicity” Pedro C. Rosado, “Immobilization of drug metabolizing enzymes in a nickel oxide foam: physico-chemical and enzymatic characterization” Samuel Guieu, “Aggregation-induced emission enhancement: principles, illustrations and applications” Paula M. Marcos, “Fluorescent ureido-dihomooxacalix[4]arene-based receptors for anions and organic ion-pair recognition” Hermínio P. Diogo, “Carvedilol and loratadine in the supercooled and glassy states: a DSC and dielectric study” Carlos F. M. Silva, “Chromones: a promising building block for medicinal chemistry” Patrícia Calado, “Dodecyl 4,6-dideoxy glycosides towards B. anthracis with low cytotoxicity” Cristina J. Dias, “Synthesis and characterization of a hybrid based on porphyrin-graphene quantum dots: a preliminary assessment towards breast cancer cells” Ana R. Monteiro, “Functionalization of graphene oxide with porphyrins and terpyridine-like compounds via non-covalent interactions” Mariana Q. Mesquita, “Photodynamic therapy of prostate cancer using chlorin and isobacteriochlorin derivatives” Susana S. Braga, “Probing the medicinal properties of 3(5)-(2-hydroxyphenyl)5(3)-styryl-1H-pyrazoles and their ruthenium complexes” Catarina I. V. Ramos, “G-quadruplex intercalative interaction of a small doubly charged ligand” João P. M. António, “Stable boron heterocycles as stimuli-responsive linkers for the preparation of targeted bioconjugates”

Poster Session 2 PC46 PC47 PC48

Rafael T. Aroso, “Structure-activity relationships of cationic imidazolyl photosensitizers for sub-micromolar inactivation of bacteria” Diana I. S. P. Resende, “Xanthone derivatives as inhibitors of P-glycoprotein and of tumor cell growth: synthesis and biological evaluation” João P. S. Ferreira, “Synthesis of 2-aroylfuro[3,2-c]quinolines from quinolonebased chalcones and evaluation of their antioxidant and anticholinesterase activities”

PC49 PC50 PC51 PC52 PC53 PC54 PC55 PC56 PC57 PC58 PC59 PC60 PC61 PC62 PC63 PC64 PC65 PC66 PC67 PC68 PC69 PC70 PC71 PC72 PC73 PC74 PC75 PC76 PC77

Joana M. D. Calmeiro, “Photodynamic therapy using thioglycerol porphyrin and phthalocyanine derivatives” Sandra Beirão, “New glycochlorins for light biomedical applications” Sara R. G. Fernandes, “New glycosylated phthalocyanines for cancer photodynamic therapy” Daniela Ribeiro, “Synthesis of new phenolic cinnamic acid derivatives and SAR evaluation of their COX-1 and COX-2 inhibitory effects in human blood” Ricardo Cristelo, “SCTC: a new orally active heparin mimetic” Daniela Pereira, “Chalcone versus flavone derivatives with in vivo antisettlement activity” Catarina Bravo, “Improving problematic antibiotics with safe metals: a combined structural and antimicrobial study of new nalidixic acid-Ca(II) frameworks” Maria João R. P. Queiroz, “Synthesis of novel methyl 3-(het)arylthieno[3,2b]pyridine-2-carboxylates by Suzuki–Miyaura cross-coupling and antitumor evaluation” Nuno A. Guerreiro Alves, “A novel spiro-β-lactam with potent anti-HIV and antiplasmodial activity” Emília Sousa, “Design, synthesis and antimicrobial activity of potential modulators of bacterial efflux pumps” Américo J. S. Alves, “Structural Insights into the distinct antimicrobial profile of spiro-β- and spiro-ɣ-lactam” Hélio M. T. Albuquerque, “Development of new AChE inhibitors” Sara Moura, “Novel semisynthetic derivatives of madecassic acid with anticancer activity” Pedro J. M. Sobral, “Novel A-ring cleaved glycyrrhetinic acid derivatives with antiproliferative activity” Vânia André, “Antibiotic coordination frameworks targeting improved activity a tactic to rejuvenate “old” quinolone antibiotics” Paula C. Alves, “Antibacterial hydrogen-bonding frameworks of pipemidic acid complexes” Pedro Brandão, “Engaging isatins in multicomponent reactions – Ugi adducts with promising biological activity” Mariana C. S. Vallejo, “Water-soluble meso-tetraarylporphyrin derivatives as potential polymeric ligands for theranostic” Bruno Franco, “Synthesis of molecular probes with a sulfonamide moiety” A. Sofia Joaquinito, “5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin: a versatile platform on the preparation of biologically active photosensitizers” Rita L. Araújo, “Searching the optical properties of corrole macrocycles as new gasotransmitters chemosensors” Joana R. M. Ferreira, “1,2,4-Triphenyl-pyrroles: synthesis, structures, and luminescent properties” Carlos J. P. Monteiro, “Nanomagnets decorated with tetrapyrrolic macrocycles: shining a light in pathogens inactivation” Paula S. S. Lacerda, “Synthesis of functional meso-triarylcorroles of A2B type” Maria G.P.M.S. Neves, “Evaluation of the gas-phase fragmentation pattern of new derivatives obtained from the reaction of β-nitro-mesotetraphenylporphyrin with p-chlorophenoxyacetonitrile” Inês Moreira, “Ohmic versus conventional heating in the synthesis of palladium(II) pyrrolidine-fused chlorins” Raquel Nunes da Silva, “Lighting-up protein and lipid aggregates” Maria I. Ismael, “Synthesis of potentially bioactive pyrazolidin-3-ones derivatives for the treatment of bipolar disorder” Letícia D. Costa, “N-Methylation of thiazolo[5,4-c]isoquinolines”

PC78 PC79 PC80 PC81 PC82 PC83 PC84 PC85 PC86 PC87 PC88 PC89 PC90

João P. C. Tomé, “Porphyrins and phthalocyanines designed for different applications” Melani J.A. Reis, “Synthetic approach to di- and trisubstituted porphyrins as templates for donor-π-acceptor derivatives” Cláudia P. S. Ribeiro, “Cationic porphyrin-cyclodextrin derivatives” Cátia I. C. Esteves, “Synthesis and luminescence properties of analogues of the green fluorescent protein chromophore” Carla Fernandes, “Chiral derivatives of xanthones: dual application in medicinal chemistry” Susana M. M. Lopes, “Meso-substituted corroles from nitrosoalkenes and dipyrromethanes” Vítor A. S. Almodôvar, “Synthesis of new N-substituted diketopyrrolopyrroles” Ana F. R. Cerqueira, “Synthesis of novel tetraoxodipyrroloporphyrins” Miguel Maia, “Towards new BACE1 inhibitors: in silico studies and synthesis” Wachirawit Udomsak, “Synthesis of new proteomimetic quinazolinone alkaloids modified at the anthranilic and tryptophan moiety” Amina Moutayakine, “Targeting MAO inhibition with novel N-propargylated chromanone derivatives” Paula S. Branco, “Synthesis of drug metabolites of abuse of Benzo Fury´s” Liza Saher, “Synthesis and anticancer activity of triazole-benzimidazolechalcone hybrids”

ABSTRACTS

Plenary Lectures

PL1

Subphthalocyanines: singular aromatic non-planar molecules Tomás Torres,a,b,c a

Department of Organic Chemistry, Autonoma University of Madrid, Cantoblanco, 28049 Madrid, Spain. IMDEA-Nanoscience, c/Faraday 9, Campus de Cantoblanco, 28049 Madrid, Spain. cInstitute for Advanced Research in Chemical Sciences (IAdChem), UAM, Cantoblanco, 28049 Madrid, Spain Email: tomas.torres@uam.es

Among the molecular building blocks used for the construction of light-powered, electroactive ensembles, subphthalocyanines (SubPcs) hold a privileged position due to their outstanding photophysical properties.1,2 These singular cone-shaped, aromatic molecules show a strong absorption in the 550-650 nm region with excitation energies above 2.0 eV, high fluorescence quantum yields, a rich redox chemistry, and low reorganization energies. Recently, SubPcs have been used as non-fullerene acceptors in bulk heterojunctions (BHJ) solar cells.2g On the other hand as part of our systematic investigation in the preparation and study of novel SubPc-based D–A systems, we have used 1,1,4,4tetracyanobuta-1,3-diene (TCBD) as partner for SubPcs. Columnar aggregates based on chiral SubPcs have been also prepared, giving rise to ferroelectric self-assembled molecular materials showing both rectifying and switchable conductivity.2a,i These chromophores have been incorporated in multicomponent systems showing a panchromatic response and allowing the tuning and controlling intramolecular FÖRSTER Resonance Energy Transfer for Singlet Fission.2j During this talk an overview of the results obtained by our group in Madrid will be given. References: 1. a) Claessens, C. G. et al., Chem. Rev., 2014, 114, 2192–2277 2. a) Guilleme, J. et al., Angew. Chem. Int. Ed. 2015, 54, 2543-2547. b) Rudolf, M. et al. Chem. Sci. 2015, 6, 4141-4147. c) Cnops, K. et al. J. Am. Chem. Soc. 2015, 137, 8991−8997. d) J. Guilleme, J. et al , Chem. Commun., 2016, 52, 9793-9796. e) Guilleme, J. et al., Chem. Commun., 2016, 52, 9793-9796. f) Urbani, M. et al., Chem. Asian J. 2016, 11, 1223-12131. g) Duan, C. et al., Angew. Chem. Int. Ed. 2017, 56, 148–152. h) Winterfeld, K. A. et al., J. Am. Chem. Soc., 2017, 139, 5520–5529. i) A. V. Gorbunov, et al., Science Advances, 2017, 3, e1701017. j) Lavarda, et al. G., Angew. Chem. Int. Ed. 2018, 57, 16291-16295.

PL2

Sugar chemistry unveiling the secrets of nature Amélia P. Rautera,b a Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 6, Campo Grande, 1749-016 Lisboa, Portugal. bCentro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 6, Campo Grande, 1749-016 Lisboa, Portugal. Email: aprauter@fc.ul.pt

In light of the latest findings on the role of the interaction of Aβ with cellular prion protein (PrPC) in Aβ-induced neurodegeneration, we show now that polyphenol C-glucosylation translates into compound inhibition of the downstream Aβ signaling pathway by disrupting PrPC-Aβ interactions and inhibiting Tau hyperphosphorylation. Also polyphenol physicochemical properties modulation is explored and our most promising results will be disclosed. By linking sugars through a C-C bond to polyphenols, their behaviour as PanAssay INterference CompoundS (PAINS) is also prevented, as demonstrated by a glucosyldihydrochalcone family, exhibiting a potent inhibitory activity of Sodium Glucose Co-Transporter 2. This enzyme mediates renal glucose reabsorption and its inhibition is recognized as a valuable approach to treat hyperglycaemia. In our experiments, dihydrochalcone C-glucosylation increases IC50 values, becoming 1000-fold higher than those of the corresponding aglycones and of the analogue O-glucoside, also demonstrating the ability of C-glucosylation for aglycone bioactivity fine-tuning. Interestingly, glycone structure does not only improve aglycone activity and pharmacokinetics, but is able to be itself the key for bioactivity as shown with dodecyl deoxy glycosides. These molecular entities are potent and selective bactericides, as demonstrated by a small library of dodecyl deoxy glycosides differing in the anomeric atom, glycone conﬁguration and deoxygenation pattern. This study led to the discovery of the first sugar-based bactericides acting over microbe phosphatidylethanolamine-rich membranes by targeting membrane lipid polymorphism. Since cell envelope ultrastructures cannot easily change without substantial loss of function, this mode of action is expected to avoid bacterial resistance.

Acknowledgements: The author is gratefully acknowledged to Fundação para a Ciência e a Tecnologia for the support of the strategic project UID/MULTI/00612/2019 of Centro de Química e Bioquímica, to the European Union for the approval of the project “Diagnostic and Drug Discovery Initiative for Alzheimer's Disease” (D3i4AD), FP7-PEOPLE-2013-IAPP, GA 612347 and to the management authorities of the European Regional Development Fund and the National Strategic Reference Framework for the support of the Incentive System—Research and Technological Development Co-Promotion Project “New drugs from sugars against Bacillus infection”, project number 21457.

PL3

Development of tools and drugs for membrane proteins involved in inflammation, immunity and cancer Christa E. Müllera,b a

Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany. b PharmaCenter Bonn, University of Bonn, 53121 Bonn, Germany Email: christa.mueller@uni-bonn.de

Purine and pyrimidine derivatives, such as the nucleotides ATP, ADP, UTP, and UDP, the nucleoside adenosine and the nucleobase adenine, are important signaling molecules, which activate cell membrane receptors termed P0 (adenine receptors), P1 (adenosine receptors), P2Y and P2X (nucleotide receptors). P0, P1 and P2Y receptors are G protein-coupled, while P2X receptors are ATP-gated ion channels. There is a metabolic link between P1 and P2 receptor agonists since the nucleotides ATP and ADP (P2 agonists) are hydrolyzed by various ectonucleotidases producing the P1 agonist adenosine. While ATP is a danger signal mediating pro-inflammatory effects, adenosine acts as a stop signal inducing anti-inflammatory and immunosuppressive activities. Despite decades of research, only few drugs for purine receptors have been approved so far. Recently, new hypes and hopes have been created in the field, mainly due to the gold rush fever in immuno-oncology. Adenosine is one of the strongest immunosuppressant agents of the innate immune system. Cancer cells and tissues can release large amounts of ATP which is immediately hydrolyzed by ectonucleotidases. These ecto-enzymes, including ectonucleotide pyrophosphatase/ phosphodiesterase 1 (NPP1, CD203a), ectonucleoside diphosphohydrolase 1 (NTPDase1, CD39), and ecto-5´-nucleotidase (CD73), are upregulated on many cancer cells leading to the production of adenosine. The cloud of adenosine formed around cancer tissues contributes to immune escape by interacting with adenosine A2A and A2B receptor subtypes (A2AAR, A2BAR) on immune cells. In addition, activation of A2BARs by adenosine enhances cancer cell proliferation, metastasis, and angiogenesis. Blockade of A2A and A2B adenosine receptors and/or inhibition of adenosine formation by blocking ectonucleotidases are being pursued as novel principles that activate the immune system to defeat cancer. Our group has focused (i) on the development and characterization of assays, tool compounds and drugs for P0, P1 and P2 receptors and ectonucleotidases, and (ii) on studies directed towards gaining structural information regarding protein-ligand interactions. Moreover, we have explored a series of orphan GPCRs related to purine-activated receptors. Recently, we have been developing tools for directly studying and inhibiting G proteins. References (selection): 1.Zhang et al. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 2014, 509, 115. 2.Zhang et al. Agonist-bound structure of the human P2Y12 receptor. Nature 2014, 509, 119. 3.Bhattarai et al., a,β-Methylene-ADP (AOPCP) derivatives and analogues: development of potent and selective ecto-5’nucleotidase (CD73) inhibitors. J. Med. Chem. 2015, 58, 6248. 4.Köse et al. Fluorescent-labeled selective adenosine A2B receptor antagonist enables competition binding assay by flow cytometry. J. Med. Chem. 2018, 61, 4301. 5.Jiang et al. A2B adenosine receptor antagonists with picomolar potency. J. Med. Chem. 2019, 62, 4032. 6.Lee et al. Development of a selective and highly sensitive fluorescence assay for nucleoside triphosphate diphosphohydrolase1 (NTPDase1, CD39). Analyst 2018, 143, 5417. 7.Rafehi & Müller. Tools and drugs for uracil nucleotide-activated P2Y receptors. Pharmacol Ther. 2018, 190, 24. 8.Hinz et al. Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors. Oncotarget 2018, 9, 13593. 9.Köse et al. An agonist radioligand for the proinflammatory lipid-activated G protein-coupled receptor GPR84 providing structural insights. J. Med. Chem., in press.

PL4

From imidazoles to chromenes: a personal journey in organic synthesis M. Fernanda Proença CQ-UM and Department of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal Email: fproenca@quimica.uminho.pt

The importance of both imidazoles1 and chromenes2 has been recognized along the past decades and was emphasized in numerous reviews and articles. These core structures are widely present in natural products and the variety and relevance of their pharmacological properties associated to their low toxicity are attractive features for medicinal chemists and a source of inspiration for the design of novel therapeutic agents. The pharmaceutical industry is also deeply aware of these important scaffolds in the search for new drug candidates. The research that has been carried out by members of the group over the last decade, involved the synthesis of imidazole derivatives through novel and simple approaches. Some compound families were tested for their biological activity, namely as anticancer agents. The chromene core was also widely studied and new fused structures were prepared, preferably through cascade reactions. A number of molecules were identified as promising anticancer agents. Part of the synthetic methods developed will be discussed in this presentation and some relevant aspects of the biological activity of a selection of new compounds will also be presented (Figure 1). R1 N

O R3

Z 3

X Y 4

X Y

O 5

Figure 1: General structure of imidazoles (1), 2-imino (Z = NH) 2-thione (Z = SH) or 2-oxo-2H-chromenes or coumarins (Z = O) (2), 2,2-disubstituted-2H-chromenes (3), 4-imino (Z = NH) or 4-oxo-4H-chromenes or chromones (Z = O) (4) and 4,4-disubstituted-4H-chromenes (5).

Acknowledgements: We acknowledge the financial support from the University of Minho, FCT – Fundação para a Ciência e a Tecnologia, I.P. for the national funds through the Strategic Projects UID/QUI/00686/2016 and UID/QUI/00686/2018 and through the Portuguese NMR network (RNRMN) (Project F-COMP-01-0124FEDER-022716 and ref. FCT PEst-C/QUI/UI0686/2011) FEDER-COMPETE.

References: 1. a) Xin-Mei Peng, Guri L. V. Damu, Rong-Xia Geng, Cheng-He Zhou, S. D. González, Medicinal Research Reviews, 2014, 34, 2, 340-437. 2. a) M. Costa, T. A. Dias, A. Brito, M. F. Proença, Eur. J. Med. Chem. 2016, 10, 123:487-507. b) R. Pratap. V. J. Ram, Chem. Rev. 2014, 114, 20, 10476-10526. c) S. A. Patil, R. Patil, L. M. Pfeffer, D. D. Miller, Future Medicinal Chemistry, 2013, 5(14), 1647–1660.

PL5

Fluorine chemistry to diagnose and cure diseases VĂŠronique Gouverneur University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road Oxford OX1 3TA (UK) Email: veronique.gouverneur@chem.ox.ac.uk

The invention of chemical reactions to create fluorine-containing molecules is an important aspect of modern medicine. Positron Emission Tomography (PET) with short-lived 18Fradiotracers is an imaging modality that can diagnose diseases, and monitor how patients respond to therapy. Moreover, the stable isotope 19F is commonly used in drug discovery to identify lead molecules and improve their properties. In this lecture, we will provide an overview of the key reactions we have developed to advance fluorine-based medicine, a rewarding process that has enhanced our fundamental understanding of fluorine chemistry, more specifically fluoride reactivity.

PL6

Activity-based glycosidase profiling in biomedicine and biotechnology Herman Overkleeft Leiden Institute of Chemistry, Leiden University, The Netherlands Email: h.s.overkleeft@chem.leidenuniv.nl

Activity-based protein profiling (ABPP) is a rapidly emerging field in chemical biology research. Enzymes that employ a mechanism in processing their substrate that involves formation of a covalent enzyme-intermediate adduct can be blocked by mechanism-based suicide inhibitors: compounds that react within the enzyme active site to form a covalent and irreversible adduct. Introduction of a reporter moiety (‘TAG’ in the below picture) yields an activity-based probe (ABP) through which enzyme activities can be discovered (comparative ABPP) and the efficacy enzyme inhibitors in complex biological systems analyzed (competitive ABPP).

retaining β-glucosidase

TAG

OH O

bead

HO HO HO

TAG

O H

HO HO HO

TAG

in-gel ABPP O

chemical proteomics

structural studies

FluoPol ABPP

structure guided conformational inhibitor design

O comparative & competitive ABPP activity based secretome profiling

Our work on ABPP development focuses on retaining glycosidases: hydrolytic enzymes able to cleave interglycosidic linkages and that do so through the formation of covalent enzyme-substrate intermediates. Configurational and functional analogues of the natural product and mechanism-based retaining beta-glucosidase inhibitor, cyclophellitol, prove to be highly versatile tools to study retaining glycosidases of various nature and origin in relation to human health and disease, but also in the field of biotechnology. In this lecture, the current state in the design, synthesis and application of synthetic cyclophellitol derivatives in studying retaining glycosidases will be presented. Discussed subjects will include 1) diagnosis of human lysosomal exoglycosidases in lysosomal storage disorders; 2) their use in screening campaigns for competitive glycosidase inhibitors and 3) application of glycosidase ABPs in the functional profiling of fungal secretomes for the discovery of glycosidases for biotechnology application. References: 1. M. D. Witte, W. W. Kallemeijn, J. Aten, K.-Y. Li, A. Strijland, W. E. Donker-Koopman, B. Blijlevens, G. Kramer, A. M. C. H. van den Nieuwendijk, B. I. Florea, B. Hooibrink, C. E. M. Hollak, R. Ottenhoff, R. G. Boot, G. A. van der Marel, H. S. Overkleeft and J. M. F. G. Aerts, Ultrasensitive in situ visualization of active glucocerebrosidase molecules, Nat. Chem. Biol. 2010, 6, 907-913. 2. L. Wu, J. Jiang, Y. Jin, W. W. Kallemeijn, C.-L. Kuo, M. Artola, W. Dai, C. van Elk, M. van Eijk, G. A. van der Marel, J. D. C. Codée, B. I. Florea, J. M. F. G. Aerts, H. S. Overkleeft and G. J. Davies, Activity-based probes for functional interrogation of retaining beta-glucuronidases, Nat. Chem. Biol. 2017, 13, 867-873. 3. D. Lahav, B. Liu, R. J. B. H. N. van den Berg, A. M. C. H. van den Nieuwendijk, T. Wennekes, A. T. Ghisaidoobe, I. Breen, M. J. Ferraz, C.-L. Kuo, L. Wu, P. P. Geurink, H. Ovaa, G. A. van der Marel, M. van der Stelt, R. G. Boot, G. J. Davies, J. M. F. G. Aerts and H. S. Overkleeft, A fluorescence polarization activitybased protein profiling assay in the discovery of potent, selective inhibitors for human non-lysosomal glucosylceramidase, J. Am. Chem. Soc. 2017, 139, 14192-14197. 4. S. P. Schröder, C. de Boer, N. G. S. McGregor, R. J. Rowland, O. Moroz, E. Blagova, J. Reijngoud, M. Arentshorst, D. Osborn, M. D. Morant, E. Abbate, M. A. Stringer, K. B. R. M. Krogh, L. raich, C. Rovira, J.-G. Berrin, G. P. van Wezel, A. F. J. Ram, B. I. Florea, G. A. van der Marel, J. D. C. Codée, K. S. Wilson, L. Wu, G. J. Davies and H. S. Overkleeft, Dynamic and functional profiling of xylan-degrading enzymes in Apergillus secretomes using activity-based probes, ACS Cent. Sci. 2019, DOI: 10.1021/acscentsci.9b00221.

Keynote Lectures

KN1

From one target to multi-target drugs: when pharmacological promiscuity becomes an advantage Fernanda Borges CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto fborges@fc.up.pt

Neurodegenerative diseases (ND) are a large group of disorders of the central nervous system with heterogeneous clinical and pathological expressions, affecting specific neuronal groups and brain signaling networks. Albeit each ND exhibits its own mechanisms and pathological hallmarks, it is consensual that their etiology is multifactorial and that neuronal death occurs as a result of a complex network of cross-talking damaging stimuli over an extended period of time. Nevertheless, no exact causes have yet been identified and the current knowledge on ND pathology is still based on a cascade of hypothesis. Furthermore, the existing single-target drugs in therapy are only palliative, have diverse side-effects, and fail to modify disease progression. For some time, drug discovery players have been questioning the success of the reductionist philosophy to ameliorate disease states with multifactorial and polygenic nature. Consequently, it is intuitive that by targeting networked signalling pathways a better regulation of the system can be achieved. One of the main limitations with this approach is the ability to define the set of targets and the design compounds that will hit the key targets with a desirable potency ratio. This is certainly a daunting challenge but given the current unmet medical needs, and the possible gains, such a venture is worthwhile. In this context, our research group has been focused in the discovery of new chemical entities based on the natural inspired scaffolds, based on one target and multi-target drug discovery approaches, for classic and new targets linked to neurodegenerative diseases. The most relevant data attained so far will be briefly depicted. Acknowledgments: The project is supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081, PTDC/MED-QUI/29164/2017/POCI-01-0145-FEDER-029164, and PTDC/MED-FAR/29391/2017/POCI-01-0145-FEDER-029391). COST action CA15135 (Multi-target Paradigm for Innovative Ligand Identification in the Drug Discovery Process) support is also acknowledged References 1.F. Mesiti, D.Chavarria, A. Gaspar, S. Alcaro, F. Borges The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease, . Eur J Med Chem 2019, 181, 111572. 2.S Benfeito, C Oliveira, C Fernandes, F Cagide, J Teixeira, R Amorim, J Garrido, C Martins, B Sarmento, R Silva, F Remião, E Uriarte, PJ Oliveira, F Borges Fine-tuning the neuroprotective and blood-brain barrier permeability profile of multi-target agents designed to prevent progressive mitochondrial dysfunction. Eur J Med Chem 2019 167, 525. 3.J.Reis, F. Cagide, M. Estrada Valencia, J. Teixeira, D. Bagetta, C. Pérez, E. Uriarte, P. J Oliveira, F. Ortuso, S.Alcaro, María I.l Rodríguez-Franco, F. Borges. Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors. Eur J Med Chem. 2018, 5;158:781 4.C. Oliveira, F. Cagide, J. Teixeira, R. Amorim, L. Sequeira, F. Mesiti, T. Silva, J. Garrido, F. Remião, S. Vilar, E. Uriarte, P. J Oliveira, F. Borges. Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors. Front Chem. 2018, 6,126. 5.J. Teixeira, F. Cagide, S. Benfeito, P. Soares, J. Garrido, I. Baldeiras, J. A Ribeiro, C. M Pereira, A. F Silva, P. B Andrade, P. J Oliveira, F. Borges. Development of a Mitochondriotropic Antioxidant Based on Caffeic Acid: Proof of Concept on Cellular and Mitochondrial Oxidative Stress Models.J Med Chem. 2017, 60(16):7084

KN2

Synthetic transformations under flow conditions Carlos A. M. Afonso Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal Email: carlosafonso@ff.ulisboa.pt

Performing reactions under continuous processes, using either high scale or microflow devices, provides valuable benefits in terms of productivity, purity and safety derived from efficient reagent mixing, heat transfer and pressure control, when compared to batch processes.1 This laboratory has been involved on the development of some synthetic methodologies based on functional groups transformations under batch conditions. In this line, will be presented some examples on the application of flow chemistry to some studied transformations under batch conditions such as enzymatic resolution, oleuropein methanolysis,2 chemoselective modification of 5‑hydroxymethylfurfural (HMF) derivatives (1),3 heterogeneous catalyzed transformation of furfural to trans-4,5-diaminocyclopent-2enones (2),4 and sequential photochemical rearrangement and hydration of N-alkyl pyridinium salts to bicyclic aziridines (3).5

Acknowledgements: We thank Fundação para a Ciência e Tecnologia (PD/BD/128316/2017, PTDC/QUIQOR/32008/2017 and UID/DTP/04138/2013), COMPETE Programme (SAICTPAC/0019/2015) for financial support. References: 1. M. B. Plutschack, B. Pieber, K. Gilmore, P. H. Seeberger, Chem. Rev., 2017, 117, 11796. 2. L. A. S. Cavaca, C. A. B. Rodrigues, S. P. Simeonov, R. F. A. Gomes, J. A. S. Coelho, G. P. Romanelli, A. G. Sathicq, J. J. Martínez, C. A. M. Afonso; ChemSusChem, 2018, 11, 2300. 3. J. M. J. M. Ravasco, C. M. Monteiro, F. Siopa, A. F. Trindade, J. Oble, G. Poli, S. P. Simeonov, C. A. M. Afonso, ChemSusChem, 2019, 12, 4629 (VIP). 4. R. F. A. Gomes, N. R. Esteves, J. A. S. Coelho, C. A. M. Afonso; J. Org. Chem., 2018, 83, 7509. 5. a) F. Siopa, J. P. M. António, C. A. M. Afonso, Org. Process Res. Dev., 2018, 22, 551. b) M. A. G. Fortunato, C.-P. Ly, F. Siopa, C. A. M. Afonso; Methods Protoc. 2019, 2, 67.

KN3

Halophytes from the salt pans of Ria de Aveiro: gourmet products with nutritional health benefits Diana C. G. A. Pinto LAQV-Requimte and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal Email: diana@ua.pt

We are witnessing an increase in saline water as well as a scarce of freshwater and these facts are stimulating the development of saline agriculture. In this context, the halophyte Salicornia ramosissima J. Woods can be highlighted because its cultivation is spreading and it is already used as gourmet food, despite its nutritional value was just recently established (Figure 1).1 Ria de Aveiro salt pans is an exceptional growing matrix for this halophyte but several other unexplored species can become, in the near future, an important substitute for the conventional crops.2 Furthermore, owing to their growing conditions, they can produce interesting bioactive compounds (Figure 1).3 From the perspective of the above mentioned, several research studies, involving other halophytic species growing in Ria de Aveiro salt pans, were scheduled and accomplished. From the unexplored halophytes that grow widely in saltmarshes of Ria de Aveiro, Puccinellia maritima (Hudson) Parl., Spartina maritima (Curtis) Fernald, Spartina patens (Aiton.) Muhl., and Limonium vulgare Mill. were chosen and their lipophilic and phenolic profiles were established.4 In this communication, the outcomes of the above-mentioned studies will be presented and discussed, aiming to highlight their potential as nutraceuticals or source of bioactive compounds.

Figure 1: A) Total amount of each class of compounds in each analyzed sample; B) New natural compounds isolated from the S. ramosissima aerial parts. Acknowledgements: Thanks are due to the University of Aveiro and FCT/MCT for the financial support for the QOPNA research Unit (UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) through national funds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement. References: 1. V. M. S. Isca, A. M. L. Seca, D. C. G. A. Pinto, H. Silva, A. M. S. Silva, Food Chem. 2014, 165, 330. 2. M. V. Faustino, M. A. F. Faustino, D. C. G. A. Pinto, Int. J. Mol. Sci. 2019, 20, 1067. 3. a) V. M. S. Isca, A. M. L. Seca, D. C. G. A. Pinto, H. Silva, A. M. S. Silva, RSC Adv. 2015, 5, 61380; b) D. Ferreira, V. M. S. Isca, P. Leal, A. M. L. Seca, H. Silva, M. L. Pereira, A. M. S. Silva, D. C. G. A. Pinto, Arabian J. Chem. 2018, 11, 70; c) D. Ferreira, D. C. G. A. Pinto, H. Silva, A. P. Girol, M. L. Pereira, Biomed. Pharmcother. 2018, 107, 283. 4. a) M. V. Faustino, M. A. F. Faustino, H. Silva, Ă&#x201A;. Cunha, A. M. S. Silva, D. C. G. A. Pinto, Molecules 2019, 24, 3796; b) Unpublished results.

KN4

Why going NANO on cancer healthcare? JoĂŁo Conde Instituto de Medicina Molecular (iMM), Faculdade de Medicina, Universidade de Lisboa Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal Email: joaodconde@gmail.com

Cancer has become the chief proving ground-breaking platforms that can be used for Precision Medicine. Determining the response profile of a tumor, detecting key driver players in tumor progression, and trying to disable those drivers with targeted therapies and engineered materials so as to â&#x20AC;&#x153;smashâ&#x20AC;? the brakes on malignant and metastatic cells to control proliferation will be the modus operandi of my group. Cancer Nanotechnology is becoming a burgeoning field and I am sure that will aim to bring up reality to the Precision Medicine initiative. It is now crucial to empower the potential of Nanomedicine to differentially combat cancer using smart and targeted platforms that mediate highly selective therapies within the tumor microenvironment. The lack of standardized means to treat and profile the tumor microenvironment calls for a paradigm shift in the way we view and treat cancer. It is in this paradigm that my presentation will focus.

KN5

Challenges in the design of oncogene and p53 expression modulators Alexandra Paulo iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649 003 Lisboa Email: mapaulo@ff.ulisboa.pt

DNA binding compounds have been widely used in cancer therapy, but their general toxicity due to lack of selectivity demands new approaches. An emerging and promising new approach has the nucleic acid four-stranded structures, known as G-quadruplexes (G4), as target. These quadruplex structures can be formed by sequences containing repetitive guanine tracks and computational human genome analysis indicate an enrichment of these sequences in regions controlling cellular proliferation, such as the promoters of protooncogenes.1 The concept of G4 targeting with small molecules is now generally accepted as a promising novel approach to anticancer therapy,1,2 with two drug candidates in clinical trials. However, the design of drug-like and selective G4-interactive small molecules faces several challenges: the highly dynamic nature of G4s; the identical chemical nature of G4 and duplex DNA; the crowded and complex nuclear environment, among others. We have approached these challenges by designing compounds to target different regions of the G4 structure. The affinity, selectivity, mode of binding and efficacy of compounds were studied using biophysical, biochemical, molecular modeling and molecular biology techniques. Our studies show that selective G4-ligands can reduce KRAS oncogene expression, as well to induce the expression of tumor suppressor p53 and apoptosis in cancer cells, at low µM concentrations.3,4 Moreover, our studies have also revealed the potential of targeting G4s in cancer stem cells, a subpopulation implicated in chemoresistance.5 In addition, we have been investigating the chemical requirements for a DNA-interactive small molecule to accumulate in the nucleus.6

Figure: Molecular simulations showing small molecules targeting the top G-quartet and loops (1.)4 or grooves (2.)5. 3. Fluorescence images of HEK293T cells incubated with two potential DNA-binders.6

Acknowledgements: To my collaborators; to COMPETE (Lisboa-01-0145-FEDER-016405) and FCT for financial support through project grants SAICTPA/0019/2015 and PTDC/QUI-QOR/29664/2017. References: 1. A. Paulo, C.C. Castillo, S. Neidle. Targeting Promoter Quadruplex Nucleic Acids for Cancer Therapy. In: Chackalamannil S, Rotella DP and Ward SE (eds.) Comprehensive Medicinal Chemistry III, 2017, vol. 5, pp. 308– 340. Oxford: Elsevier. 2. A.R. Duarte, E. Cadoni, A.S. Ressurreicao, R. Moreira, A. Paulo. ChemMedChem. 2018,13, 869. 3. H. Brito, A.C. Martins, J. Lavrado, E. Mendes, A.P. Francisco , S.A. Santos, S.A. Ohnmacht, N.S. Kim, C.M.P. Rodrigues, R. Moreira, S. Neidle, P.M. Borralho, A. Paulo. PlosOne 2015, 10, e0126891. 4. J. Lavrado, H. Brito, P.M. Borralho, S.A. Ohnmacht, N.S. Kim, C. Leitão, S. Pisco, M. Gunaratnam, C.M.P. Rodrigues, R. Moreira, S. Neidle, A. Paulo. Sci. Rep. 2015, 5, 9696. 5. E. Mendes, E. Cadoni, F. Carneiro, M.B. Afonso, H. Brito, J. Lavrado, D.J.V.A. Santos, J.B. Vítor, S. Neidle, C.M.P. Rodrigues, A. Paulo. ChemMedChem 2019, 14, 1325. 6. I.F.A. Mariz, S. Pinto, J. Lavrado, A. Paulo, J.M.G. Martinho, E.M.S. Macoas. Phys. Chem. Chem. Phys. 2017, 19, 10255.

KN6

Opicapone, a long-acting anti-parkinsonian drug. From in silico simulations to in human trials. P. Nuno Alma, Patrício Soares-da-Silva Department of Research and Development, BIAL-Portela & Cª, S.A, 4745-457 Coronado (S. Mamede & S. Romão), Portugal. Email: nuno.palma@bial.com

Opicapone1 is an efficacious anti-parkinsonian drug, which is characterized by a safe profile and an exceptionally long duration of action in vivo.2,3 Parkinson’s disease (PD) is a neurological disorder resulting from the degeneration of dopaminergic neurons, with consequent reduction in striatal dopamine levels and emergence of characteristic motor symptoms. This condition is commonly treated with prescribed Levodopa, which enters the brain and is thereof converted into dopamine. However, Levodopa is also quickly metabolized in the peripheric circulation and is ineffective if given alone. Opicapone is a potent inhibitor of catechol-O-methyltransferase (COMT), one of the enzymes responsible for the metabolic deactivation of Levodopa, and is effective at improving the PD motor symptoms, by increasing the bioavailability of Levodopa, when the two are given together. In this presentation, the mechanism of action of Opicapone is discussed at the molecular level, using advanced computational chemistry and compartmental pharmacokinetics/pharmacodynamics simulations. It is shown how the unique chemical characteristics of this molecule and the outstanding residence time of its drug-enzyme association4 are determinant of the long duration of pharmacological action, observed in human clinical trials.2,3 A link is established between first-principles computational chemistry simulations and late-stage clinical observations in human subjects. References: 1. L. E. Kiss, H. S. Ferreira, L. Torrão, M. J. Bonifácio, P. N. Palma, P. Soares-da-Silva, D. A. Learmonth, J. Med. Chem. 2010, 53, 3396. 2. L. Almeida, J. F. Rocha, A. Falcão, P. N. Palma, A. I. Loureiro, R. Pinto, M. J. Bonifácio, L. C. Wright, T. Nunes, P. Soares-da-Silva, Clin. Pharmacokinet. 2013, 52, 139. 3. J. F. Rocha, L. Almeida, A. Falcão, P. N. Palma, A. I. Loureiro, R. Pinto, M. J. Bonifácio, L. C. Wright, T. Nunes, P. Soares-da-Silva, British J. Ckin. Pharmacol. 2013, 76, 763. 4. P. N. Palma, M. J. Bonifácio, A. I. Loureiro and P. Soares-da-Silva, J Comput. Chem. 2012, 33, 970.

KN7

Heterocycles from nitrosoalkenes, azoalkenes and 1-azadienes Teresa M. V. D. Pinho e Melo CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal Email: tmelo@ci.uc.pt

Conjugated nitrosoalkenes and azoalkenes are effective and versatile building blocks for the construction and functionalization of heterocyclic systems.1 This lecture aims to present our contribution to the chemistry of these synthetic scaffolds illustrating the structural diversity that can be achieved by exploring their chemical behavior which key feature is the strong electrophilic character. Thus, nitrosoalkenes and azoalkenes have been mainly used as electron-deficient heterodienes in hetero-Diels–Alder cycloaddition or as Michael-type acceptors in conjugate 1,4-addition reactions. Conjugated nitrosoalkenes and azoalkenes, including 3-tetrazolyl- and 3-triazolyl derivatives, were used for the alkylation of five-membered heterocycles namely pyrroles, dipyrromethanes, indoles, pyrazoles and furans. Tryptamines were prepared via heteroDiels-Alder reaction of nitrosoalkenes with indoles and used in the synthesis of bcarbolines by the Pictet-Spengler approach. New routes to dipyrromethanes, bis(indolyl)methanes, bis(pyrazolyl)methanes, bis(imidazolyl)methanes and tetrapyrrolic compounds have been developed. Details of this chemistry and the results regarding the biological evaluation of some of the new heterocycles will be presented and discussed.2 The synthesis and reactivity of steroidal N-sulfonyl-1-azadienes toward carbonyl compounds under enamine catalysis leading to new chiral pentacyclic and hexacyclic steroids will also be presented (Scheme 1).3 X

Exploring Furan's Chemistry

N R2 N

From α-halooximes and hydrazones

O X = NR'/O

R1 N

HN N N N NH2 Tryptophan N analogues N HN N HN

OH N R2

O NYH

N N N NR'

Het

N N ArN

Het = Pyrrole, Indole, Pyrazole

N H

R''

Het HYN

HON

HYN R

TsN Me

N N

Bis(pyrazolyl)methanes

N H

N ArN

Het Het

Het = Pyrrole, Indole, Pyrazole, Imidazole, Benzimidazole

TsN

AcO

NR'

Bis(indolyl)methanes

NOH N N

Me H

NYH

NH HN

Bilanes

n = 1-4

R'N

R1 R2

NH HN

Y = O or NR' X = Cl or Br

NH HN

NYH

Dipyrromethanes

TsN Me H

NH HN

Ar R1 R2

NYH

Corroles

β-Carbolines

NH HN

From α,α-dihalooximes and hydrazones

R R

O NOH

NAr N

Ketone / Pyrrolidine MW, 140 ºC, 10 min

X = O, S, NMe

Scheme 1: Heterocycles from nitrosoalkenes, azoalkenes and 1-azadienes. Acknowledgements: The Coimbra Chemistry Centre (CQC) is supported by the Portuguese Foundation for Science and Technology (FCT), Project UID/QUI/00313/2019. References: 1. S. M. M. Lopes, A. L. Cardoso, A. Lemos, T. M. V. D. Pinho e Melo, Chem. Rev. 2018, 118, 11324. 2. Pinho e Melo et al. Tetrahedron 2011, 67, 8902; Eur. J. Org. Chem. 2012, 2152; Eur. J. Org. Chem. 2014, 7039; J. Org. Chem. 2014, 79, 10456; Synlett 2014, 25, 423; Synlett 2014, 25, 2868; Eur. J. Org. Chem. 2015, 6146; Eur. J. Med. Chem. 2015, 93, 9; Monatsh. Chem. 2016, 147, 1565; ChemMedChem 2017, 12, 701; Eur. J. Org. Chem. 2017, 4011; Bioorg. Med. Chem. 2017, 25, 1122; Eur. J. Med. Chem. 2018, 143, 1010; Eur. J. Med. Chem. 2019, 179, 123; Monatsh. Chem. 2019, 150, 1275. 3. S. M. M. Lopes, C. S. B. Gomes, T. M. V. D. Pinho e Melo, Org. Lett. 2018, 20, 4332 .

Invited Oral Communications

IOC1

Heterocyclic probes: design, synthesis and application in chemosensing and molecular bioimaging Susana P. G. Costa, M. Manuela M. Raposo Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal spc@quimica.uminho.pt

Heterocyclic derivatives are a versatile class of compounds with a wide range of applications in diverse areas such as medicinal or materials chemistry due to their biological activity, as well their optoelectronic properties. Our earlier studies showed that the optical properties of p-conjugated heterocyclic systems could be tuned through functionalization of the heterocycles, changing its electronic nature or position on the heterocyclic system.1 This increases the potential for several ground-breaking applications of these molecules namely as sensitive and selective optical chemosensors and fluorescent bioimaging probes.2 Recent results from our research group concerning the design, synthesis and characterization of novel imidazole and thiophene derivatives 1-2 (Figure 1), as optical chemosensors, NIR chromophores and/or molecular bioimaging probes will be presented and discussed. R1 N R2

N H

CHO

n = 1-2

R1, R2, R3 = (hetero)aromatic

Figure 1: Imidazole derivatives as fluorescent bioimaging probes (left) and thiophene derivatives as optical chemosensors (right). Acknowledgements: Thank are due to Fundação para a Ciência e Tecnologia (Portugal) and FEDERCOMPETE for financial support through Centro de Química (PEst-C/QUI/UI0686/2013 and PEstC/QUI/UI0686/2016) and a PhD grant to R.C.M. Ferreira (SFRH/BD/86408/2012). The NMR spectrometer Bruker Avance III 400 is part of the National NMR Network (PTNMR) and is partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). References: 1. a) Raposo, M. M. M.; Sousa, A. M. R. C.; Kirsch, G.; Cardoso, P.; Belsley, M.; Matos Gomes, E.; Fonseca, A. M. C. Org. Lett. 2006, 8(17), 3681-3684. b) Pina, J.; Seixas de Melo, J. S.; Batista, R. M. F.; Costa, S. P. G.; Raposo, M. M. M. Phys. Chem. Chem. Phys. 2010, 12(33), 9719-9725. 2. a) Batista R. M. F.; Oliveira E.; Costa S. P. G.; Lodeiro C.; Raposo M. M. M. Org. Lett. 2007, 9, 3210. b) Raposo, M. M. M.; García-Acosta, B.; Ábalos, T.; Calero; P.; Martínez-Manez, R.; Ros-Lis, J. V.; Soto, J. J. Org. Chem. 2010, 75(9), 2922–2933. c) Marín-Hernández, C.; Santos-Figueroa, L. E.; Moragues, M. E.; Raposo, M. M. M., Batista, R. M. F.; Costa, S. P. G.; Pardo, T.; Martínez-Máñez, R.; Sancenón, F. J. Org. Chem. 2014, 79(22), 10752-10761. d) Okda, H. E.; Sayed, S. E.; Ferreira, R. C. M.; Costa, S. P. G.; Raposo, M. M. M., Martínez-Máñez, R. Sancenón, F. Dyes Pigments 2018, 159, 45-48. e) Okda, H. E.; Sayed, S. E.; Ferreira, R. C. M.; Otri, I.; Costa, S. P. G.; Raposo, M. M. M., Martínez-Máñez, R. Sancenón, F. Dyes Pigments 2019, 162, 303-308. f) Okda, H. E.; Sayed, S. E.; Ferreira, R. C. M.; Gonçalves, R. C. R. Costa, S. P. G.; Raposo, M. M. M., Martínez-Máñez, R. Sancenón, F. New J. Chem. 2019, 43, 7393-740.

IOC2

5-Substituted (thio)barbiturates as proteasome inhibitors for cancer therapy: design, synthesis and biological evaluation Sara Hummeid,a João Serrano,a Romina Guedes,b,c Paulo Almeida,a Adriana O. Santos,a Rita Guedes,b Samuel Silvestrea,c a

CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal. b iMed.Ulisboa and Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal. c CNC, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal. Email: sms@ubi.pt

The ubiquitin proteasome and immunoproteasome systems have been defined as potential targets in the treatment of a range of clinical conditions, such as inflammation, neurodegenerative diseases and cancer, particularly, haematological malignancies. A variety of chemical synthesized and natural products have exhibited proteasome inhibitory activity from which three were approved for use in multiple myeloma treatment.1 2Thioxoimidazolidin-4-one arylaldehyde derivatives were described as novel noncovalent proteasome inhibitors in a recent study.2 Considering the structural similarity of thiobarbituric acid and 2-thioxoimidazolidin-4-one systems, 5-substituted (thio)barbiturate derivatives may be interesting in the discovery of a novel class of proteasome inhibitors with potential anticancer interest. In this context, several barbiturate derivatives with a chemical scaffold similar to merbarone demonstrated promising antiproliferative effects in different cancer cell lines.3,4 In our study, we designed and efficiently synthesized a range of 5-substituted (thio)barbiturate derivatives through one or two-step synthesis.4 Then, a proteasome inhibition assay was performed where 5-[1-[2-(4-nitrophenyl)-hydrazinyl]ethylidene]barbiturate (Figure 1) showed interesting inhibitory activity. Consequently, antiproliferative effect of the same compound in healthy and cancer cell lines was evaluated and compared with bortezomib, an approved proteasome inhibitor. Although the promising compound showed cytotoxicity against healthy and cancer cell lines, it was less potent than bortezomib. Furthermore, molecular docking studies were performed intending to explain the proteasome inhibitory observed results.5

Figure 1: Chemical structure of 5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]barbiturate. Acknowledgements: We thank FCT - Foundation for Science and Technology for supporting the project “Smallmolecule inhibitors of human proteasome: a step forward in anticancer drug discovery" (PTDC/QEQMED/7042/2014; PI: Prof. Rita Guedes) as well as the project UID/Multi /00709/2013. We also thank FEDER funds through the POCI - COMPETE 2020 - Operational Programme Competitiveness and Internationalisation in Axis I Strengthening research, technological development and innovation (Project POCI-01-0145-FEDER-007491). References: 1. C. L. Soave, T. Guerin, J. Liu, Q. P. Dou, Cancer Metastasis Rev. 2017, 36, 717. 2. R. Maccari, R. Ettari, I. Adornato, A. Nass, G. Wolber, A. Bitto, F. Mannino, F. Aliquo, G. Bruno, F. Nicolo, Previti, S. Grasso, M. Zappala, R. Ottana, Bioorg. Med. Chem. Lett. 2018, 28, 278. 3. H. S. A. El-Zahabi, M. M. A. Khalifa, Y. M. H. Gado, A. M. Farrag, M. M. Elaasser, N. A. Safwat, R. AbdelRaouf, R. K. Arafa, Eur. J. Pharm. Sci. 2019, 130, 124. 4. J. Figueiredo, J. L. Serrano, E. Cavalheiro, L. Keurulainen, J. Yli-Kauhaluoma, V. M. Moreira, S. Ferreira, F. Domingues, S. Silvestre, P. Almeida, Eur. J. Med. Chem. 2018, 143, 829. 5. a) R. A. Guedes, P. Serra, J. A. R. Salvador, R. C. Guedes, Molecules. 2016, 21, 927. b) R. A. Guedes, Aniceto, M. A. P. Andrade, J. A. R. Salvador, R. C. Guedes, Int. J. Mol. Sci. 2019, 20, 5326.

S. R. C. N.

IOC3

Synthesis, photophysical properties and applications of pyrano3-deoxyanthocyanin dyes Vânia Gomes, Ana Sofia Pires, Nuno Mateus, Victor Freitas, Luis Cruz LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal. Email: luis.cruz@fc.up.pt

Flavylium-based dyes represent a huge family of natural and synthetic pigments, which includes anthocyanins, 3-deoxyanthocyanins and their derivatives such as pyranoanthocyanins. Beyond their important biological properties (e.g. antioxidant, antiproliferative activities), they are responsible for the coloration of many of flowers, vegetables and fruits ranging from yellow to blue. In recent years, our research group has been to dedicate to the synthesis, isolation and characterization of natural and bioinspired pyranoflavylium–type dyes (Scheme 1).1-3 These dyes are very interesting for many applications because of their pH-dependence chromatic features and photophysical properties.4 In this work, a series of novel pyrano-3-deoxyanthocyanin dyes have been synthesized and characterized in terms of fluorescence properties and thermodynamic constants driven by pH variations. The knowledge of those properties could be important towards their biomedical and food applications mainly as fluorescent probes for in vivo imaging and as pH-sensors for food intelligent packaging. Energy

Cosmetic

Biomedical

Food

Scheme 1: Chemical synthesis and application fields of pyrano-3-deoxyanthocyanin dyes. Acknowledgements: This research was supported by a research project grant (PTDC/OCE-ETA/31250/2017) with financial support from FCT/MCTES through national funds and co-financed by FEDER, under the Partnership Agreement PT2020 (UID/QUI/50006/2019 - POCI/01/0145/FEDER/007265). References: 1. L. Cruz, V. Petrov, N. Teixeira, N. Mateus, F. Pina and V. De Freitas, J. Phys. Chem. B, 2010, 114, 1323213240. 2. J. L. C. Sousa, V. Gomes, N. Mateus, F. Pina, V. de Freitas and L. Cruz, Tetrahedron, 2017, 73, 60216030. 3. V. Gomes, N. Mateus, V. de Freitas and L. Cruz, Dyes Pigm., 2019, 167, 60-67. 4. A. L. Pinto, L. Cruz, V. Gomes, H. Cruz, G. Calogero, V. de Freitas, F. Pina, A. J. Parola and J. Carlos Lima, Dyes Pigm., 2019, 170, 107577.

IOC4

Harnessing the power of resin acids for innovative antimicrobial research Vânia M. Moreiraa,b,c a

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Portugal. cCenter for Neuroscience and Cell Biology, University of Coimbra, Portugal E-mail: vmoreira@ff.uc.pt

Humans have employed resins for esthetic, ceremonial, or therapeutic uses for millennia.1 Gum rosin in particular, has an annual worldwide production of more than 1 million tons and is used as an ingredient for inks, varnishes, adhesives, cosmetics, medicines and chewing gums. The ecological role of resins is protective, i.e, when trees are cut, the volatiles in the resin evaporate leaving the solid portion that contains “resin acids”, which shelter them from external stress and invaders, promoting healing. Our research has revealed that these “resin acids”, belonging to the class of abietanetype diterpenoids, have antimicrobial and anti-biofilm activity towards gram positive bacteria and can be exploited for human use.2 Through chemistry, we have created a library of over 50 new chemically pure “resin acids” derivatives, that includes, to the best of our knowledge, the most potent agents reported within their class so far.3,4 It is noteworthy that this effect is accompanied by a good tolerability profile and low potential for spreading resistance. Moreover, combination of these compounds with nanocellulose, an advanced biopolymer with excellent mechanical properties and biocompatibility, resulted in innovative and cost-effective functional surfaces, bearing broad spectrum of action against bacteria, high biocompatibility and no cross-resistance with drug-resistant strains.5 This presentation will detail the outcomes of our work with this class of compounds and further illustrate how natural products and their derivatives foster innovation in antimicrobial research. Acknowledgements: Business Finland (former TEKES, project 1297/31/2016), the Huonekalusäätio, Finland (2014, 2015) and Tenovus Scotland, UK (project S18-23). References 1. Klemens, F., Dieter, G. "Resins, Natural". Ullmann's Encyclopedia of Industrial Chemistry, 2000. 2. Fallarero, A., Skogman, M., Kujala, J., Rajaratnam, M., Moreira, V. M., Yli-Kauhaluoma, J., Vuorela, P. Int. J. Mol. Sci. 2013, 14, 12054-12072. 3. Manner, S., Vahermo, M., Skogman, M. E., Krogerus, S., Vuorela, P. M., Yli-Kauhaluoma, J., Fallarero, A., Moreira, V. M. Eur. J. Med. Chem. 2015, 102, 68-79. 4. Moreira, V.M., Vahermo, M., Fallarero, A., Yli-Kauhaluoma, J., Vuorela, P.” WO 2016/051013 A1, Apr. 7th, 2016. 5. G. Hassan, N. Forsman, X. Wan, L. Keurulainen, L. M. Bimbo, L.-S. Johansson, N. Sipari, J. YliKauhaluoma, S. Stehl, C. Werner, P. E. J. Saris, M. Österberg, V. M. Moreira, ACS Sust. Chem. Eng., 2019, 7, 5002-5009.

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Helping mother nature through medicinal chemistry in lato sensu: new nature-inspired antifouling compounds obtained by synthesis Elisabete R. Silva,a,b Cátia Vilas Boas,c,d Ana Rita Neves,c,d Francisca Carvalhal,c,d Alexandre Campos,c Vitor Vasconcelos,c Madalena Pinto,c,d Emília Sousa,c,d Joana R. Almeida,c Marta Correia-da-Silvac,d a

BioISI - Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande C8 bdg, Lisboa, 1749-016 Portugal bCERENA - Centro de Recursos Naturais e Ambiente, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001, Lisboa, Portugal cCentro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n 4450-208 Matosinhos, Portugal d Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal.

Email: m_correiadasilva@ff.up.pt

Marine biofouling creates enormous economic, environmental and human health costs, which are increasing every day due to the massive increase of ocean-related activities. The antifouling paints in use are continuing releasing persistent, bioaccumulative, and toxic biocides to the oceans and there is a practical and urgent need of identifying innovative environmentally friendly and non-toxic technologies to combat marine biofouling. The most promising alternatives for fouling protection focus on the development of coatings whose active ingredients are natural products or lab-synthesized products inspired in natural compounds.1 In this sense, our research group has been pursuing the synthesis of Natureinspired compounds with antifouling activity.2,3,4,5 Nearly 190 compounds were synthesized and screened in the last three years. However, only compounds able to discourage the attachment of mussels larvae with EC50 values <25 μg/mL (US Navy recommendations) and LC50/EC50>15, with low ecotoxicity to nontarget organisms and low bioaccumulative potential were considered by us as promising antifouling candidates. From those, three compounds (a polyphenolic acid, a bile acid, and a xanthone derivative) emerged with the necessary balance between the efficacy and eco-friendly properties adding to their feasible syntheses. These compounds were successfully incorporated in polyurethane and silicone-based marine coatings without losing their antifouling properties and exhibiting low release to seawater 2,6. Proteomic studies revealed, as putative targets of the xanthone derivative, two collagen proteins (PreCols), which are related to byssal thread properties such as resistance to tension and shock absorber.7 From this work, it is possible to conclude that the application of Medicinal Chemistry principles to solve environmental problems becomes an extremely useful tool and fulfills the broad sense of the concept of this scientific area. Acknowledgements: Support for this work was provided by FCT through the Strategic Funding UID/Multi/04423/2019 (CIIMAR) and UID/MULTI/04046/2019 (BioISI) and the project PTDC/AAG-TEC/0739/2014 (reference POCI-01-0145FEDER-016793) supported through national funds provided by FCT and ERDF through the COMPETE - POFC programme and the RIDTI Project -9471. A. R. Neves and C. Vilas Boas acknowledge FCT for the Grants SFRH/BD/114856/2016 and SFRH/BPD/88135/2012, respectively. References: 1. C. Vilas-Boas, E. Sousa, M. M. M Pinto, M. Correia-da-Silva, Biofouling, 2017, 33, 927-942. 2. A. R. Neves, J. R. Almeida, F. Carvalhal, A. Câmara, S. Pereira, J. Antunes, V. Vasconcelos, M. Pinto, E. R. Silva, E. Sousa, M. Correia-da-Silva, Overcoming environmental problems of biocides: Synthetic bile acid derivatives as a sustainable alternative. Ecotoxicology and Environmental Safety, 2020, 187, 109812. 3. J. R. Almeida, J. Moreira, D. Pereira, S. Pereira, J. Antunes, A. Palmeira, V. Vasconcelos, M. Pinto, M. Correia-da-Silva, H. Cidade, Science of The Total Environment 2018, 643, 98-106. 4. J. R. Almeida, M. Correia-da-Silva, E. Sousa, J. Antunes, M. Pinto, V. Vasconcelos, I. Cunha, Scientific Reports, 2017, 7, 42424. 5. C. Vilas Boas, S. Cravo, E. R. Silva, E. Sousa, M. Pinto, M. Correia-da-Silva. Eco-friendly potential of new promising antifouling synthetic compound. Frontiers in Marine Science, 2018. DOI: 10.3389/conf.FMARS.2018.06.00061. ISSN: 22967745. 6. A. E. Ferreira, C. Vilas Boas, J. R. Almeida, E. Sousa, M. Pinto, M. Correia-da-Silva, M. J. Calhorda, E. R. Silva. Inhibition of marine biofoulants settlement by new biomimetic coatings. Frontiers in Marine Science, 2018. DOI: 10.3389/conf.FMARS.2018.06.00061. ISSN: 2296-7745. 7. NPAT325'18 - Oxygenated xanthone derivatives as antifouling agents (PPP 61236 V depósito 17/12/2018). Inventors: M. Correia-da-Silva, E. Sousa, M. Pinto, J. R. Almeida, V. Vasconcelos, E. R. Silva.

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Dihydropyrazolylquinolones and furoquinolines from quinolone-based chalcones as potential antioxidant and anticholinesterase agents Vera L. M. Silva,a* João P. S. Ferreira,a Pedro M. O. Gomes,a Susana M. Cardoso,a Filipe A. Almeida Paz,b Artur M. S. Silvaa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. b CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. Email: verasilva@ua.pt

Quinolones, quinolines and pyrazolines (dihydropyrazoles) are nitrogen heterocycles of recognized importance in medicinal chemistry due to their remarkable biological properties. Quinolones and quinolines are known to possess antibacterial, neuroprotective and antioxidant activities.1,2 In turn, pyrazolines are recognized for their anti-inflammatory and antioxidant activities, among other important medicinal properties.3 On the other hand, chalcone-type compounds are excellent scaffolds for synthetic manipulations to get other relevant compounds.4 Herein we present our recent developments on the synthesis of (E)-3-(3-aryl-3-oxoprop-1-en-1-yl)quinolin-4(1H)-ones 1 and their transformation into dihydropyrazolylquinolones 2 and furoquinolines 3 (Scheme 1). The potential of compounds 2 and 3 to inhibit oxidative stress and acetylcholinesterase activity (i.e, two key events in Alzheimer’s disease)5 was evaluated in vitro in chemical models. Antioxidant activity of compounds 2 and 3 was assessed through the ability to scavenge the free radicals 2,2-diphenyl-1-picrylhydrazyl, 2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) and nitric oxide (DPPH•, ABTS+• and NO•, respectively) while the acetylcholinesterase inhibitory activity of 3 was determined through the Ellman’s method.6 Among these compounds, dihydropyrazolylquinolones showed significant activity as free radical scavengers while compounds 3a (R=H) and 3c (R = 4-OMe) showed promising inhibitory ability towards AChE. More details concerning the synthesis, structural characterization and structure-activity relationship (SAR) studies of compounds 1-3 will be presented and discussed in this communication.

Scheme 1: Transformation of quinolone-based chalcones 1 into dihydropyrazolylquinolones 2 and furoquinolines 3. Acknowledgements: We thank to University of Aveiro and FCT/MEC for the financial support to the QOPNA research project (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020), financed by national funds and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement and to the Portuguese NMR Network. Vera L. M. Silva thanks funding from national funds through the FCT-I.P., in the framework of the execution of the program contract provided in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/2016 of 29 August, as amended by Law no. 57/2017 of 19 July.

References: 1. a) X.-M. Chu, C. Wang, W. Liu, L.-L. Liang, K.-K. Gong, C.-Y. Zhao, K.-L. Sun, Eur. J. Med. Chem. 2019, 161, 101. b) G. S. da Silva, M. Figueiró, C. F. Tormena, F. Coelho, W. P. Almeida, J. Enzyme Inhib. Med. Chem. 2016, 31, 1464. 2. J. Greeff, J. Joubert, S. F. Malan, S. Dyk, Bioorg. Med. Chem. 2012, 20, 809. 3. V. L. M. Silva, J. Elguero, A. M. S. Silva, Eur. J. Med. Chem. 2018, 156, 394. 4. H. M.T. Albuquerque, C. M. M. Santos, J. A. S. Cavaleiro, A. M.S. Silva, Curr. Org. Chem. 2014, 18, P2750. 5. J. B. Melo, P. Agostinho, C. R. Oliveira, Neurosci. Res. 2003, 45, 117. 6. G. L. Ellman, K. D. Courtney, V. Andrés Jr., M. R. Featherstone, Biochem. Pharmacol. 1961, 7, 88.

Portuguese Award for Best Young Organic Chemist 2019

Award

The role of the formyl group on the β-modification of porphyrinic macrocycles Nuno M. M. Moura LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal Email: nmoura@ua.pt

The importance of porphyrins in nature and in different application fields is responsible for the considerable work involving porphyrin derivatives. The great attention devoted to the synthesis and functionalization of porphyrins and analogous is related with their unique properties, such as synthetic versatility, thermal stability, large π-electron systems and photochemical and photophysical properties.1 Today, the chemical and physical properties displayed by these tetrapyrrolic macrocycles render them strong candidates for applications in a wide range of fields. Their use as catalysts, advanced biomimetic models for photosynthesis, new electronic materials, drugs or as sensors is already wellestablished by the scientific community.2 The usefulness of this type of macrocycles can be improved through the adequate introduction of appropriate functional substituents groups like the formyl at one of the βpyrrolic positions that have been considered an excellent and versatile template for further synthetic modifications through a wide range of approaches such as Wittig, Knoevenagel, cycloaddition reactions and others.3 Herein, it will be discussed synthetic strategies developed in our group, using 2-fomyl5,10,15,20-tetraphenylporphyrin as template giving access to benzoporphyrins and βfunctionalized porphyrins bearing chalcone-type, pyridine, pyrazole, imidazole and oligopyridines moieties.4

Scheme 1: β-functionalization of porphyrin macrocycle from 2-formyl-5,10,15,20-tetraphenylporphyrin. Acknowledgements: The authors are grateful to University of Aveiro and FCT/MCT for the financial support for QOPNA research Unit (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020), through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. The research contract of NMM Moura (REF.-048-88-ARH/2018) is funded by national funds (OE), through FCT. References: 1. S. Hiroto, Y.Miyake, H. Shinokubo, Chem.Rev. 2017, 117, 2910. 2. Handbook of Porphyrin Science, K. M. Kadish, K. M. Smith, R. Guilard (Eds.) Vols. 10-12, World Scientific Publishing Co: Singapore, 2010. 3. A. F. R. Cerqueira, N. M. M. Moura, V. V. Serra, M. A. F. Faustino, A. C. Tomé, J. A. S. Cavaleiro. M. G. P. M. S. Neves, Molecules 2017, 22, 1269. 4. a) N. M. M. Moura, M. A. F. Faustino, M. G. P. M. S. Neves, F. A. A. Paz, A. M. S. Silva, A. C. Tomé, J. A. S. Cavaleiro, Chem. Commun. 2012, 48, 6142. b) N. M. M. Moura, C. Nuñez, S. M. Santos, M. A. F. Faustino, J. A. S. Cavaleiro, M. G. P. M. S. Neves, J. L. Capelo, C. Lodeiro, Inorg. Chem. 2014, 53, 6149. c) N. M. M. Moura, C. Nuñez, M. A. F. Faustino, J. A. S. Cavaleiro, M. G. P. M. S. Neves, J. L. Capelo, C. Lodeiro, J. Mater. Chem. C, 2014, 2, 4772. d) N. M. M. Moura, C. Nuñez, S. M. Santos, M. A. F. Faustino, J. A. S. Cavaleiro, F. A. A. Paz, M. G. P. M. S. Neves, J. L. Capelo, C. Lodeiro, Chem. Eur. J. 2014, 20, 6684. e) N. M. M. Moura, C. Ramos, I. Linhares, M. A. F. Faustino, A. Almeida, J. A. S. Cavaleiro, F. M. L. Amado, C. Lodeiro, M. G. P. M. S. Neves, RSC Adv. 2016, 6, 110674. f) N. M. M. Moura, I. F. A. Mariz, J. A. S. Cavaleiro, A. M. S. Silva, C. Lodeiro, J. M. G. Martinho, E. M. S. Maçôas, M. G. P. M. S. Neves, J. Org. Chem. 2018, 83, 5282. g) N. M. M. Moura, M. Esteves, C. Vieira, G.M.S.R.O. Rocha, M. A. F. Faustino, A. Almeida, J. A. S. Cavaleiro, C. Lodeiro, M. G. P. M. S. Neves, Dyes Pigm. 2019, 160, 361.

Oral Communications

OC1

Fast color switching materials using photochromic fusednaphthopyrans C. Sousa, P. Coelho Chemistry Center - Vila Real, Universidade de TrĂĄs-os-Montes e Alto Douro, Vila Real, Portugal Email: pcoelho@utad.pt

Naphthopyrans are the main photosensitive compounds used to create photochromic lenses that darken under sunlight. UV irradiation of common uncolored naphthopyrans for less than 1 minute, at room temperature, generates two thermally unstable colored species (TC and TT) that fade with different speed to the initial uncolored state. The formation of a variable amount of the slow fading TT isomer ensures a high color intensity, under UV, but originates a globally slow color fading in the dark, with a persistent residual color that can extend the complete discoloration of the lens to near 8 min. The linkage of the naphthalene core to the pyran double bond provides photochromic fused-naphthopyrans that can only form the fast fading TC isomer, under UV, and thus affords a fast and complete color fading in the dark. This structural change is very effective to suppress the undesired residual color but it also confers strain to the molecule which can lead to a too fast color fading affording a very slow concentration of the colored species and thus a weak coloration. We present a new uncolored photochromic fused-naphthopyran that can be easily prepared from naphthols and but-2-yn-1,4-diols, in one step, can be dispersed in soft polymers (0.8%), provide an intense orange coloration under UV irradiation (or sunlight) (Abs=0.7) and return completely to the uncolored state in just 2 min, at room temperature. The use of this compound allows a faster adaptation of the materialâ&#x20AC;&#x2122;s coloration to the surrounding UV-light intensity, without compromising the color intensity, an important feature to create high performance photochromic ophthalmic lenses.

Acknowledgment:This work was funded by the R&D Project DynamicDye - Light responsive naphthopyrans with faster switching speed, with reference POCI-01-0145-FEDER-028532 and PTDC/QUI-QOR/28532/2017 financed by the European Regional Development Fund (ERDF) through COMPETE 2020 - Operational Program for Competitiveness and Internationalization (POCI) and by Foundation for Science and Technology (FCT).

OC2

Lead to target: a computational approach to identify the protein targets of molecules with known experimental biological activity Tatiana F. Vieira, Rita P. Magalhães, Sérgio F. Sousa UCIBIO/REQUIMTE – BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal Email: sergiofsousa@med.up.pt

A central problem in medicinal chemistry is the identification of the protein targets to which a specific molecule binds or interacts. Every year thousands of new molecules are tested experimentally for potential biological activity, particularly antimicrobial or anti-cancer. These molecules result from the continuous research efforts in organic synthesis on specific classes of compounds from many organic chemistry groups, from studies on plants leading to the identification of new phytochemicals, from compounds identified in the marine environment, and from new molecules obtained from other natural sources. Their activity is tested against specific organisms, cell lines, or other experimental models. Through these studies, some (if not many) of these molecules come to exhibit promising biological activity that justifies further study and investment. However, a major bottleneck comes at this stage. For these molecules to be improved, in a rational and effective way, knowledge on the specific target (enzyme, receptor, protein, etc) on which they act at the molecular level is required. While some in vivo or in vitro strategies can be used to narrow down the list of possible protein targets, it is often a guess and test game that typically relies on the similarity with previous known compounds or intuition. Both these strategies are based directly or indirectly on the previous known actives for specific targets, and are conceptually biased, favoring established knowledge, in disfavor of novelty. However, it is important to keep present that the initial motivation for the biological activity-testing of all these molecules is to identify novel promising scaffolds, yet unexplored, with potential pharmacological, economic and social value. So, it is important to develop unbiased approaches to the problem of target identification. Bioinformatics, computational biology and computational chemistry are disciplines that are growing in size and potentiality at an impressive rate, with borders that touch and intertwine, resulting in a large and continuous body of knowledge that is starting to fill, spanning from the organism, to the cellular, molecular, atomic and electronic level. Here, we describe a multi-disciplinary computational approach that we have been developing at BioSIM in collaboration with different experimental groups, to identify the potential binding targets of specific molecules with confirmed experimental activity. For that we combine the information from large bioinformatics databases covering the full proteome of specific organisms of interest or different cell-lines, with the structural information obtained from the Protein Data Bank, molecular dynamics, inverse virtual screening, protein-ligand docking, molecular dynamics, free energy calculations and Quantum Mechanics/Molecular Mechanism Methods.

Acknowledgements: We thank FCT for support through projects UID/MULTI/04378/2019, IF/00052/2014, PTDC/ASP-AGR/30154/2017

OC3

Small organic fluorophores. Structure–property correlation of solid emissive compounds Patrícia A. A. M. Vaz,a,b João Rocha,b Artur M. S. Silva,a Samuel Guieua,b a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. b CICECO Aveiro-Institute of Materials, Department of Chemistry, University of Aveiro, Portugal Email: patriciavaz@ua.pt

Luminescent small organic chromophores, in particular fluoroborates complexes, have attracted significant attention in recent years due to their potential optoelectronic and biological applications. Solid-emissive dyes are limited because most of them tend to suffer a self-quenching in concentrated solution or in solid state. An elegant approach to improve luminescence in solid state relies on the aggregation-induced emission enhancement (AIEE) effect where chromophores which are poorly emissive in dilute solution become highly fluorescent or phosphorescent in the solid state. Based on many theoretical and experimental studies, the restriction of intramolecular rotations (RIR) has been proposed as the main cause for the solid emitters examples. In the search of allorganic luminophores efficient in solid state, halogen bonding (XB) that promotes intersystem crossing through the heavy atom effect and thus induces phosphorescence emission has emerged as an important factor.1 Combining XB and AIEE effect and structural modifications in some fluoroborates complexes to minimize the effects of IR in solid state has been our strategy to develop new luminescent small organic materials.as promising blue-emitting solid materials (Figure 1).2 We synthetized and studied different families of potential organic dyes (chalcone, benzophenone and benzimidazole derivatives) decorated with halogen atoms as wells as fluoroborates complexes with structural features to produce blue-emitting solid materials. The boron complexation with the ligand, the occurrence of halogen bonding, the complementarity or competition with hydrogen bonding, their importance for the organization of the compounds in the crystal packing and their influence on the luminescent properties will be presented and discussed.

Figure 1: Strategies to develop new luminescent small organic materials. Acknowledgements: Thanks are due to University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program, and the European Union (FEDER program) via the financial support to the QOPNA research project (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020), to CICECO-Aveiro Institute of Materials (FCT Ref. UID/CTM/ 50011/2019), financed by national funds through the FCT/MCTES, to the Portuguese NMR Network, and to the PAGE project (CENTRO-01-0145-FRDER-000003). SG is supported by national funds (OE), through FCT, I.P., in the scope of the framework contract foreseen in the numbers 4, 5, and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19, and PAAMV by the FCT (SFRH/BD/99809/2014). References: 1. a) Y. Kubota, K. Kasatani, H. Takai, K. Funabiki, M. Matsui, Dalton. Trans. 2015 44, 3326. b) F. Ciardelli, G. Ruggeri, A. Pucci, Chem. Soc. Rev., 2013, 42, 857. C) G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi, G. Resnati, G. Terraneo, Chem. Rev.2016 116 2478. d) O. Bolton, K. Lee, H. J. Kim, K. Y Lin, J Kim, Nat. Chem. 2011, 3, 205. 2. a) P A. A. M. Vaz; J. Rocha; A. M. S. Silva, S. Guieu, New J. Chem. 2018, 42, 18166. b) P A. A. M.Vaz; J. Rocha; A. M. S. Silva, S. Guieu, Cryst. Eng. Comm, 2017, 19, 2202. c) P A. A. M.vaz; J. Rocha; A. M. S. Silva, S. Guieu, New. J. Chem., 2016, 40, 8198.

OC4

On the use of molecular interaction fields to predict drug-resistance Ana I. Mata,a# Nuno G. Alves,a# João P. Luís,a# Carlos J. V. Simões,a,b Rui M. M. Britoa,b a

CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal. bBSIM Therapeutics, Instituto Pedro Nunes, Coimbra, Portugal. #Authors with equal contribution. Email: ana.mata@student.uc.pt

The human immunodeficiency virus type 1 (HIV-1) is one of the most studied viruses and its protease (HIV1-Pr) has been one of the main targets of HIV-1 antiretroviral therapy. Due to the high mutation rate of HIV1-Pr, the use of protease inhibitors (PI) has to be constantly monitored and adjusted, since first-line regimen PIs are not successful in controlling more resistant, current strains. To avoid subjecting patients to regimens that might not be effective against HIV-1, the use of in silico tools to predict drug-resistance is becoming a more common and desirable practice. Such tools often take a target HIV1-Pr sequence and, through the use of machine-learning techniques, try to predict mutations conferring resistance to a certain drug (sequence-based approach), or even analyse the impact of mutations on the protein structure of HIV1-Pr that may result in resistance (structure-based approach).1 Even though sequence-based tools achieved a more widespread adoption due to the speed and simplicity of the output obtained from genotypic data analysis, the detailed structural context of mutated amino acid residues, which is directly intertwined with the determinants of target-inhibitor interactions accounting for susceptibility or resistance, is largely lost. In contrast, structure-based methodologies focus their searches on the three-dimensional target structure, involving the analysis of the structural and physicochemical environment of inhibitor binding sites, in some cases even taking the dynamics of the target protein into consideration. However, these methods are often computationally expensive and time-consuming. As such, we set out to develop a fast, accessible sequence-to-structure method to predict resistance to antivirals – using HIV1-Pr as first case-study.2 Herein we reveal a novel GRID-based approach to the prediction of drug-resistance, making extensive use of the Molecular Interaction Fields (MIFs) concept. In essence, MIFs may be defined as the spatial variation of interaction energies between a molecular structure and specific types of chemical probes laid out on a 3D grid encompassing that structure. MIFs have been extensively applied in a broad range of Computational Chemistry endeavors, including binding site detection, pharmacophore design and searches, and molecular docking. The inclusion of a MIF generation and comparison step in a predictive workflow, immediately after the structural modelling of a target HIV1-Pr sequence, is expected to provide an instant snapshot of PI’s binding site with sufficient atomic detail to probe mutation-induced structural and chemical changes conferring resistance.3 To test this approach, we set up a workflow comprising the following main steps: (1) perform processing and structural modelling of an HIV1-Pr sequence; (2) generate MIFs for the input structural model and compare them with those obtained for a known HIV1-Pr reference structure (binding site region) that is susceptible to all PIs; and (3) predict the input sequence/structure as “resistant” or “susceptible”. Performance tests were run to evaluate the proposed method using test sequences with known phenotype, retrieved from Stanford’s University HIV Database.4 Receiver Operating Characteristic (ROC) curves were built for subsets with different levels of resistance, showing areas under the ROC curve close to 1 in all cases. The results obtained across different test subsets allowed us to fine-tune the classification threshold, yielding sensitivities in the range of 0.93-0.99 and specificity of 0.99. The promising results obtained with our MIF-based approach to drug-resistance prediction entice us to further focus on using a more dynamic set of susceptible references. This inclusion could expand the horizons of our method’s predictions, accounting for the features of different PIs in HIV-1 treatment – as well as look into the possibility of broadening the scope of the workflow to other viruses and bacteria. Acknowledgements: Ana I. Mata, Nuno G. Alves, and João P. Luís thank the MedChemTrain PhD programme (PD/00147/2013) in Medicinal Chemistry – Foundation for Science and Technology (FCT), Ministry of Science, Technology, and Higher Education (MCTES) – for the grant of PhD fellowships. References: 1. D. J. Baxter, M. W. Chasanov, L. J. Adams, J. AIDS Clin. Res. 2016, 7, 581; I. Weber, D. Kneller, A. Wong-Sam, Future Med. Chem. 2015, 7(8), 1023. 2. J. Vercauteren, A. M. Vandamme, Antiviral Res. 2006, 71(2-3), 335; G. F. Hao, G. F. Yang, C. G. Zhan, Drug Discov. Today. 2012, 17(19-20), 1121. 3. A. Artese, S. Cross, G. Costa, S. Distinto, L. Parrotta, S. Alcaro, F. Ortuso, G. Cruciani, WIREs Comput. Mol. Sci. 2013, 3, 594. 4. S. Y. Rhee, M. J. Gonzales, R. Kantor, B. J. Betts, J. Ravela, R. W. Shafer, Nucleic Acid Res. 2003, 31(1), 298.

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Heterogeneous catalysts for biodiesel production: microwave versus conventional assisted method Graça Rocha, Mariana Almeida, Castigo Chame, André Francisco University of Aveiro, 3810-193 Aveiro, Portugal grrocha@ua.pt

The world of today is facing remarkable changes due to the incorrect behaviour of the human being. One direct consequence of this negligence is the global warming caused by the abundance of CO2 in the atmosphere. As such, the search for renewable and safer resources with less environmental impact is now mandatory. An alternative fuel must be economically competitive, environmentally acceptable and readily available.1 Biodiesel is in accordance with these conditions and its production can be performed in the presence of acidic, basic and enzymatic catalysts. Homogeneous catalysts are widely used, but the huge disadvantages associated with its utilisation encouraged the usage of heterogeneous catalysts in the last decades.2 In this perspective, the features of the tetravalent metal phosphates and phosphonates are fundamental to act as efficient solid catalysts.3

Yield (%)

80 60

a-NaZrP 76.4

72.0

62.8 38.0

100

81.0 80.2 60.0

Sunflower oil

Corn oil

25.2

Yield (%)

100

60.0 55.8

73.8

81.2

78.5 83.0 Sunflower oil

Corn oil

40 20

20 0

g-NaZrP

86.3 80.8

CV (80 °C; 6h)

MW (80 °C; 1h)

MW MW (80 °C; 2h) (100 °C; 2h)

CV MW MW MW (100 °C; 6h) (100 °C; 1h) (100 °C; 2h) (120 °C; 2h)

Yield (%)

Our work started with the synthesis, characterization and catalytic evaluation of the a- and g-zirconium phosphates (a- and g-ZrP) and the correspondent sodium exchanged phosphates (a-NaZrP and gNaZrP) in the transesterification reactions of sunflower oil using the conventional reflux method (CV). The fatty acid methyl esters (FAMEs) formed with a-NaZrP and g-NaZrP were identified by GC-MS and quantified by GC. The best yields were obtained after varying sequentially the molar ratio methanol:oil, temperature, mass ratio catalyst:oil and reaction time. Then, the former best reaction conditions achieved with the sunflower oil were tested in the transesterification reactions of corn oil. After the above results, the transesterification reactions of the sunflower and corn oils were performed by the microwave assisted method (MW). With this method, only the temperature and reaction time parameters were studied. The best yields were obtained after 2 hours of reaction at 100ºC with the a-NaZrP and after 2 hours of reaction at 120ºC with the g-NaZrP for the two oils. No FAMEs were observed with a- and g-ZrP or in the blank reactions either with the sunflower or corn oils. In a parallel study, the a- and g-ZrP, zirconium phenylphosphonate (ZrPhP) and zirconium tungstate phosphate (ZrWP) were tested in the esterification reaction of palmitic acid using the CV. The quantification of methyl palmitate was done by GC. The best yield was reached with g-ZrP (45%). A blank reaction was also performed (20%). Thus, the reaction conditions were optimized by varying sequentially the amount of g-ZrP, molar ratio palmitic acid:methanol and temperature. With the best reaction conditions a yield of 86% and 47% was reached with Methyl palmitate / g-ZrP 100 and without the catalyst, respectively. Then, the esterification 86.0 78.0 71.6 80 reaction of the palmitic acid was performed by the MW. With this 60.1 60 method, only the reaction time parameter was studied. The best 40 yields were obtained after 3 hours of reaction at 100ºC. The best 20 yields of FAMEs were obtained with a-NaZrP and g-NaZrP for the 0 CV MW MW MW transesterification reactions and with g-ZrP for the esterification (100 °C; 6h) (100 °C; 1h) (100 °C; 2h) (100 °C; 3h) reactions. As can be confirmed by the graphics, very good results were achieved using the MW considering that the reaction time was substantially decreased for both situations, which implies a considerable decrease in energy consumption. The structure of the catalysts and the optimization of the reaction conditions will be discussed in detail during the presentation. References: 1. M. Mittelbach, Eur. J. Lipid Sci. Tech. 2015, 117, 1832; Chuah L. F., Klemeš, Yusup S., Bokhari A., Akbar M. M., J. Clean Prod. 2017, 146, 181. 2. Diamantopoulos N., Panagiotaras D., Nikolopoulos D., J. Thermodyn. Catal. 2015, 6(1), 1; Avhad M. R., Marchetti J. M., Renew. Sust. Energ. Rev. 2015, 50, 696. 3. Pica M., Catalysts 2017, 7, 190.

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Abietane diterpenoids from Plectranthus spp.: a source of lead molecules Patrícia Rijoa,b a

CBIOS-Center for Research in Biosciences & Health Technologies, Universidade Lusófona de Humanidades e Tecnologias, 1749-024 Lisboa, Portugal. bInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal Email: patricia.rijo@ulusofona.pt

Natural products from medicinal plants represent an important source of novel therapeutic substances to fight severe diseases including cancer and infections.1 The Plectranthus genus (Lamiaceae family) represents a large and widespread group of species with a diversity of traditional uses for the treatment of several ailments. Diterpenoids are commonly found in Plectranthus spp., and have a widespread spectrum of biological activity, namely antimicrobial or anticancer properties.2 Considering this, several extraction methods were tested to optimize the extraction of the antimicrobial diterpenoid 7α-acetoxy-6β-hydroxyroyleanone (Roy, Figure 1). Supercritical fluid extraction (SFE) proved to be the method of choice, delivering the extraction of Roy from P. grandidentatus. Other basic requirements approaches for the development of pharmaceutical formulations based on Roy as a lead molecule, suggests that polymorphism is not likely to be an issue in the development pharmaceutical formulations using Roy.3 Protein kinase C (PKC) family isoforms have been the focus of intense research, and are recognized as therapeutic targets in anticancer drug development. These kinases are classified into three groups according to their regulatory domain structure and cofactors requirement for activation: classical, novel, and atypical PKCs. Considering this, a small library of abietane derivatives was studied for their ability to activate PKC isoforms from classical (alpha, α; beta, β), novel (delta, d; epsilon, e) and atypical (zeta, z) subfamilies, thought a previously developed yeastbased screening assay to search for modulators of PKC isoforms.4 The results obtained revealed potent activators of PKC family proteins, namely: a selective activator of PKCd, the 7α-acetoxy-6βbenzoyloxy-12-O-benzoylroyleanone (RoyBz, Figure 1). The patented diterpenoid RoyBz was prepared using Roy as starting material. RoyBz potently inhibited the proliferation of colon cancer cells by inducing a PKCd-dependent mitochondrial apoptotic pathway involving caspase-3 activation. The results indicate that RoyBz targets drug resistant cancer stem cells, in HCT116 colon cancer cells, preventing tumor dissemination and recurrence. These results point to promising activators of PKCs with high potency and isoform-selectivity that may emerge from the exploitation of this new family of abietane diterpenoids [4]. Molecular docking studies are currently ongoing to further identify new selective abietane diterpenoids as new PKC modulators. Overall, the described results shows that indeed the Plectranthus genus is a high potential source of lead molecules. Further studies are on going to use these abietane diterpenoids lead molecules, which arises from this genus, for the development of new drugs.

Figure 1: Roy and RoyBz structures. Acknowledgements: We thank to Fundação para a Ciência e a Tecnologia (FCT), Portugal through UID/DTP/04567/2019. References: 1. Nat Chem Biol 2007, 3, 351. 2. Ladeiras, D.; Monteiro, C.; Pereira, F.; Reis, C.; Afonso, C.; Rijo, P. Curr. Pharm. Des. 2016, 22 (12), 1682–1714. 3. Bernardes CES, Garcia C, Pereira F, Mota J, Pereira P, Cebola MJ, Reis CP, Correia I, Piedade FM, Piedade MEM da, Rijo P. Mol. Pharm. 2018, 15(4): 1412–1419. 4. Bessa C, Soares J, Raimundo L, Loureiro JB, Gomes C, Reis F, Soares ML, Santos D, Dureja C, Chaudhuri SR, LopezHaber C, Kazanietz MG, Gonçalves J, Simões MF, Rijo P, Saraiva L. Cell Death Dis 2018; 9.

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Tetrapyrrole-based catalysts for oxidative transformations through sustainable processes M. J. F. Calvete, G. Piccirillo, M. E. S. Eusébio, M. M. Pereira CQC, Department of Chemistry, University of Coimbra, Coimbra, Portugal Email: mcalvete@qui.uc.pt

Metal complexes of tetrapyrrolic macrocycles (TPMs) are known to be excellent biomimetic oxidation catalysts in a variety of reactions,1 being the degradation of organic pollutants2,3 and the production of value added compounds,4 the leading topics of research (Scheme 1). Particularly, emphasis is given to promote sustainable processes using non-toxic oxidants (e.g. O2 or H2O2) and the heterogeneization of the macrocyclic catalytic complexes. The presence of pollutants, namely antibiotics and pesticides, in the environment, even at very low concentrations, is a major problem in our days, since their continuous input constitutes a potential risk for aquatic and terrestrial organisms, namely by the development of multi-resistant bacteria, in the case of antibiotics, or long- term toxicity, in the case of pesticides. Given their common recalcitrant nature, research has been directed towards the application of advanced oxidation processes(AOPs),3 for the destruction of these pollutants in waters,through generation of hydroxyl and other radicals to oxidize the recalcitrant, toxic and non-biodegradable pollutants to several by-products and eventually to inert end-products.5 In this communication, we include our recent accomplishments on the synthesis of metal complexes of tetrapyrrole-based catalysts and their application in valuable oxidative transformations, namely in the degradation of antibiotics (e.g. trimethoprim) using O2 or H2O2 as non-toxic oxidants. Both the homogeneous TPM-based catalysts and their heterogenized counterparts showed high efficiency in the degradation of the antibiotic. Reaction kinetics and mechanism parameters, along with structural determination of products (UPLC-MS/MS) and their ecotoxicity studies were performed and the results are herein presented.

Figure 1: Oxidative transformations based on tetrapyrrolic based catalysts. Acknowledgements: We thank the Fundação para a Ciência e Tecnologia (FCT) and FEDER (European Regional Development Fund) for financial support with UID/QUI/00313/2019 and POCI-01-0145-FEDER027996. G.P. thank the FCT and CATSUS program for the PhD grant (PD/BD/135532/2018). References: 1. M. M. Pereira, L. D. Dias, M. J. F. Calvete, ACS Catal., 2018, 8, 10784. 2. L. Fernández, V. I. Esteves, Â. Cunha, R.J. Schneider, J.P.C. Tomé, J. Porphyrins Phthalocyanines, 2016, 20, 150. 3. M. J. F. Calvete, G. Piccirillo, C. S. Vinagreiro, M. M. Pereira, Coord. Chem. Rev., 2019, 395, 63. 4. C. A. Henriques, A. Fernandes, L. M. Rossi, M. F. Ribeiro, M. J. F. Calvete, M. M. Pereira, Adv. Funct. Mater, 2016, 26, 3359. 5. O. Gonzalez, C. Sans S. Esplugas, J. Hazard. Mater., 2007, 146, 459.

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Novel antiproliferative N-dodecyl glucuronamide-based nucleosides inducing apoptosis in chronic myeloid leukemia cells Nuno M. Xavier,a,b Rita Gonçalves-Pereira,a,b Radek Jordac a Centro de Quimica e Bioquimica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, Portugal. bCentro de Quimica Estrutural, Faculdade de Ciências, Universidade de Lisboa. cLaboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacky University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic. Email: nmxavier@fc.ul.pt

Synthetic nucleosides, nucleotides and analogs are relevant groups of molecules in anticancer drug discovery. A number of nucleos(t)ide analogs reached clinical application for the treatment of various types of cancer and their effect is based on their propensity to be incorporated into DNA and/or to inhibit essential enzymes for DNA replication or nucleotide biosynthesis, inducing inhibition of cell division.1-3 There are however some drawbacks associated with their use, namely their low oral bioavailability and the resistance that cancer cells frequently exert towards their action.2,3 Hence, the development of nucleos(t)ide-based structures that may circumvent these issues is of considerable relevance. While structural variations at the nucleobase moiety have been well exploited, modifications at the sugar moiety or the use of uncommon glycosyl units have been relatively less considered strategies in the access to novel nucleos(t)ide analogs. In this context, in this communication the synthesis and anticancer evaluation of novel nucleosides having D-glucuronamide motifs, which are rather unusual glycosyl moieties in nucleoside chemistry, and containing a N-dodecyl chain is presented (Figure 1). The synthetic methodologies used glucofuranurono-6,3-lactone as precursor, which was converted in few steps into N-dodecyl 1,2-di-O-acetyl furanuronamide or pyranuronamide derivatives for further N-glycosidation with uracil or 2-acetamido-6-chloropurine. Antiproliferative evaluation revealed the significant activities exhibited by some molecules in chronic myeloid leukemia (K562) and in breast cancer (MCF-7) cells with GI50 values in the micromolar concentration range and in some cases comparable or lower than those of a standard drug, turning them prospective anticancer lead compounds. Further studies showed the ability of the most active molecules to induce or activate apoptosis in K562 cells.

Figure 1. General structures of the synthesized N-dodecyl glucuronamide-based nucleosides. Acknowledgements: We thank Fundação para a Ciência e Tecnologia for financial support through the FCT Investigator Program, the exploratory project IF/01488/2013/CP1159/CT0006 and the strategic projects UID/MULTI/00612/2013 and UID/MULTI/00612/2019.

References: 1. W. B. Parker Chem. Rev. 2009, 109, 2880. 2. L. P. Jordheim, D. Durantel, F. Zoulim, C. Dumontet, Nat. Rev. Drug. Discov. 2013, 12, 447-464. 3. J. Shelton, X. Lu, J. A. Hollenbaugh, J. H. Cho, F. Amblard, R. F. Schinazi, Chem. Rev. 2016, 116, 14379.

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Exploring halogen-free aminopyridines as suitable scaffolds for direct access to azaindoles A. Sofia Santos, M. Margarida Martins, M. Manuel B. Marques LAQV-Requimte and Department of Chemistry, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica (Portugal) Email: asb.santos@campus.fct.unl.pt

Azaindoles are heterocyclic structures that when properly functionalized can possess a wide range of medicinal applications. Metal-catalyzed reactions constitute a very modern topic in organic synthesis and are highly useful for the construction and functionalization of these aminopyridine-containing heterocycles.1 Reactions like, the well-known Sonogashira, Heck, and Suzuki cross-couplings have been used on the synthesis of azaindoles. As well as, other methods involving metal-catalyzed reactions such as the Cacchi and Lautens methods. The metal-catalyzed C–H activation reaction has been scarcely explored in the assembly of azaindole core, as well as on its functionalization.2 Unlike other common metal-catalyzed reactions, C−H activation usually involves cleavage of a C−H bond, to create a new C−C, C−O or C−N bond. When applied to azaindole synthesis, metal-catalyzed reactions usually require previous halogenation of aminopyridines, which are low yielding and poor regioselective. C−H activation reaction rely on the activation of a C−H bond present in the aromatic ring, thus this method allows use of commercially available starting materials, while avoiding the halogenation step.3 On the follow-up of our previous work using amino-halopyridines to attain several azaindole derivatives via Heck reaction, we investigated of a new methodology using nonfunctionalized aminopyridines.4 The method consists on the formation of imine/enamine intermediates followed by in situ C–H activation/functionalization reaction to afford the desired azaindoles (Scheme 1). Furthermore, synthesis of 4-zaindole and 6-azaindole scaffolds was attained in a regioselective manner. (Scheme 1).5

Scheme 1: Azaindole synthesis via C-H activation/functionalization reaction. Acknowledgements: This work was supported by the Associate Laboratory for Green Chemistry- LAQV which is financed by national funds from FCT/ MCTES (UID/QUI/50006/2019) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER - 007265). The National NMR Facility is supported by FC&T (ROTEIRO/0031/2013 – PINFRA/22161/2016, co-financed by FEDER through COMPETE 2020, POCI, and PORL and FC&T through PIDDAC). We thank to the FC&T for fellowship PD/BD/142876/2018. References: 1. Dias Pires, M. J.; Poeira, D. L.; Marques, M. M. B. European J. Org. Chem. 2015, 2015, 7197. 2. Santos, A.; Mortinho, A.; Marques, M. Molecules 2018, 23, 2673. 3. Roudesly, F.; Oble, J.; Poli, G. J. Mol. Catal. A Chem. 2017, 426, 275. 4. Pires, M. J. D.; Poeira, D. L.; Purificação, S. I.; Marques, M. M. B. Org. Lett. 2016, 18, 3250. 5.A. Sofia Santos, M. Margarida Martins, M. Manuel B. Marques, Org. Lett., 2019, submitted

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Epigenetic drug discovery: design, synthesis and biological evaluation of novel EZH2 inhibitors against cancer Filipa Ramilo-Gomes,a,b Sharon D. Bryant,c Riccardo Martini,d Thierry Langer,d Sheraz Gul,e Oliver Keminer,e Luís Sobral,f Rita C. Guedes,b M. Matilde Marquesa a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049001 Lisboa, Portugal. b iMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. c Inte:Ligand Software Entwicklungs und Consulting, Mariahilferstrasse 74B, 1070 Vienna, Austria. d Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria. eFraunhofer IME-SP, Schnackenburgallee 114, 22525 Hamburg, Germany. f Hovione Farmaciência SA, Sete Casas, 2674-506 Loures, Portugal. Email: filipa.ramilo.gomes@tecnico.ulisboa.pt

Epigenetic pathways are being recognized as determinants to cancer development and progression. Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that catalyzes the trimethylation of lysine 27 in Histone 3 (H3K27me3), a process that facilitates chromatin compaction and gene silencing.1 The overexpression of EZH2, the catalytic subunit of PRC2, is implicated in the development and progression of a variety of cancers with the worst prognosis. Thus, the therapeutic targeting of EZH2 emerged as a hot topic and the development of selective small-molecule EZH2 inhibitors is currently a promising research challenge for drug discovery.2 A combination of state-of-the-art techniques, from computational drug design to synthetic methodologies and biological testing are being used to develop the new molecules. We performed a computer-aided drug design campaign to design new EZH2 inhibitors using LigandScout.3 A panel of unique pharmacophore models were generated, validated and optimized. The prioritized models were used for two hit finding campaigns: Virtual Screening and De Novo Design. For the Virtual Screening approach, several databases (e.g., DrugBank, NCI, MuTaLig Chemotheca, and our in-house libraries) were computed and screened. Interesting virtual hit molecules with high inhibition potential were found and tested in order to determine their EZH2 profiles. Notably, we found several hits with inhibition rates comparable to the reference compounds (in clinical trials). In parallel, we started a De Novo Design campaign based on selected pharmacophore models and we found a new scaffold for EZH2 inhibitors. Those from de novo design are being synthesized. The potential toxicity issues are also being assessed through metabolism studies. Finally, selectivity and binding mode of the most promising compounds will be elucidated. The best drug candidates are expected to proceed to in vivo testing. Acknowledgements: This work was supported by grant PD/BD/128320/2017 from Fundação para a Ciência e a Tecnologia (FCT) and projects UID/QUI/00100/2019, UID/DTP/04138/2019, PTDC/QUI-QAN/32242/2017, and SAICTPAC/0019/2015, funded by national funds through FCT and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. This communication is based upon work from COST Action CA15135, supported by COST. References: 1. A. Brooun, K. S. Gajiwala, Deng, Y.-L, et al. Nat. Comm. 2016, 7 11384 2. K. H. Kim and C. W. M. Roberts, Nat Med. 2016, 22 128–134 3. LigandScout Molecular Design Software from InteLigand GmbH (http://www.inteligand.com)

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Exploring heterocyclic frameworks – small molecules, endless potential Carolina S. Marques,a Anthony J. Burkea,b a

Centro de Química de Évora (CQE & LAQV-REQUIMTE), University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000 Évora, Portugal. bChemistry Department, School of Science and Technology, University of Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal. Email: carolsmarq@uevora.pt

In a general way, from the health care point of view, people are living longer and most important, healthier lives. However, a shadow persists when we think about the actual causes of world mortality, and serious challenges to global health remain, ranging from pandemics, prohibitive costs of care, complex diseases, etc. With our mind focused on uncurable and mortal complex diseases (like cancer and neurodegenerative ones), we strongly believe that development of new targeting drugs is definitively an advantage in improving therapeutic efficacy, safety and even resistance profiles. Heterocyclic units are common in many commercial drugs.1 These structures are quite modular and can be easily manipulated to improve pharmacological, pharmacokinetic, toxicological and other important drug properties. In the last ten years our group has been active in the synthesis of new privileged heterocyclic scaffolds, focused on the search of promising new compounds with significative bioactivity, taking into account the creation of new processes bearing atom efficiency, time and energy saving2. Special effort was made for the synthesis of new 3,3-disubstituted oxindole derivatives (Figure 1). In this presentation we would like to reveal our latest findings concerning the synthesis of such privileged frameworks, like new innovative synthetic methodologies and their potential as cholinesterase inhibitors. Arylation Reactions! enantioselective 3-hydroxy-3-aryl-substituted oxindoles

Ketone protection group!

Reactivity on the aryl ring! Petasis reactions - benzylamine derivatives substrate screening enantioselective

X R

3,3-disubstituted oxindole derivatives

N R

increasing reactivity acetal-type oxindoles

Y O

N-Substituents effect! screening frameworks click chemistry

Figure 1: 3,3-Disubstituted oxindole derivative frameworks. Acknowledgements: The authors gratefully acknowledge the following funding sources: the INMOLFARM Molecular Innovation and Drug Discovery (ALENT-07-0224-FEDER-001743) of the FEDER-INALENTEJO program; Fundação para a Ciência e a Tecnologia (FCT) for funding through the strategic project PEstOE/QUI/UI0619/2019, including a post-doc grant to C.S.M. (SFRH/BPD/92394/2013); COST action 15135, Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig). References: 1. A. J. Burke, C. S. Marques, N. Turner, G. J. Hermann, Active Pharmaceutical Ingredients in Synthesis: Catalytic Processes in Research and Development, 1st Ed., Wiley-VCH, Weinheim, 2018. 2. a) C. S. Marques, A. Locati, J.P. P. Ramalho, A. J. Burke, Tetrahedron 2015, 71, 3314. b) C. S. Marques, S. E. Lawrence, A. J. Burke, Synlett 2018, 29, 497. c) C. S. Marques, A. J. Burke, Eur. J. Org. Chem. 2016, 806. d) H. Viana, C. S. Marques, C. A. Correia, K. Gilmore, L. Galvão, L. Vieira, P. H. Seeberger, A. J. Burke, ChemistrySelect 2018, 3, 11333. e) C. S. Marques, A. J. Burke, ChemCatChem 2016, 8, 3518.

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N4,N9-disubstituted 4,9-diaminoacridines as potential multi-stage antimalarials Mélanie Fonte,*a Natália Fagundes,*a Ana Gomes,a Ricardo Ferraz,a,b Cristina Prudêncio,b,c Maria João Araújo,a Paula Gomes,a Cátia Teixeiraa a

LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal; b Ciências Químicas e das Biomoléculas, Escola Superior de Saúde, Politécnico do Porto, 4200-072 Porto, Portugal; c i3S – Instituto de Investigação e Inovação em Saúde da Universidade do Porto, 4200-393 Porto, Portugal. *These authors contributed equally to this work Email: catia.teixeira@fc.up.pt

Malaria is one of the deadliest infectious diseases in the world and was responsible for 435 000 deaths in 2017, namely by Plasmodium falciparum species.1 Antimalarial drugs are the unique weapon to fight this disease once there is no vaccine yet. Generally antimalarial chemotherapy targets mainly the pathogenic blood stage in humans. However, there is an urgent need of new, economic and safe drugs in order to: (i) block parasite transmission to the vectors, (ii) target parasite forms that, for some species, remain transiently dormant in the liver, and (iii) overcome the resistance against artemisinin-based treatments emerging in some vulnerable population in Africa. Consequently, malaria eradication is only possible with the discovery of new multi-targets drugs.2 Mepacrine (MP, Scheme 1), the first synthetic antimalarial drug, was widely employed but it was rapidly superseded by chloroquine (CQ, Scheme 1), whose efficiency, bioavailability, and safety were far superior. By “dissecting” the chemical structure of QN, the acridine moiety of MP can be seen as the fusion between CQ and the heterocycle core of primaquine (PQ, Scheme 1), another emblematic antimalarial, active against all liver forms of the parasite, and gametocytes. In this context, and based on the fact that one fast and low-cost strategy to accelerate antimalarials development is to recycle classical pharmacophores, the aim of this work is the development a yet unexplored multi-step synthetic route towards 4,9-diaminoacridines (Scheme 1).3 These can be regarded as respectively corresponding to the fusion between CQ and PQ derivatives. As expected, the preliminary in vitro results showed that the new compounds preserved the activity of the parent drugs, with activity against blood-stage, as in CQ, as well as against liver forms similarly to PQ.

Scheme 1: Schematic representation of the synthesis of the target compound.3

Acknowledgements: We thank the Fundação para a Ciência e Tecnologia for financial support through grants UID/QUI/50006/2019 and PTDC/BTM-SAL/29786/2017. References: 1. World Health Organization, World Malaria Report, 2017. 2. Teixeira, C. et al. Chem Rev. 2014, 114, 11164-11220. 3. Fonte, M. et al. Tetrahedron Lett., 2019, 60, 1166-1169.

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Synthesis and structural modulation of tetrapyrrolic macrocycles: potential probes for PET and MRI imaging? Sara M.A. Pinto,a Vanessa A. Tomé,a Diana M.P Gomes,a Antero.J. Abrunhosa,b Carlos.F.G.C Geraldes,a Mariette M. Pereiraa a

Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal. bInstitute for Nuclear Sciences Applied to Health (ICNAS/CIBIT), University of Coimbra, Coimbra, Portugal. Email: smpinto@qui.uc.pt

Molecular imaging allows the creation of visual representations, through the use of a single functional molecule, of several parts of the human body. It supports the detection of early stage tumors, tumor growth processes, pharmacokinetics and drug action mechanisms. Among them we highlight the “noninvasive” in vivo imaging “high- end” probes based technologies, e.g. Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI).1,2 However, the lack of in vivo stability and selectivity of the available molecular probes is still a great problem. Therefore, the development of new synthetic processes for preparing alternative probes with higher selectivity and sensitivity for in vivo molecular targets, is a great challenge.3,4 Herein we report the latest findings of Coimbra Catalysis & Fine Chemistry Laboratory on the development of new tetrapyrrolic macrocycles based probes for potential application in PET Molecular Imaging and redox responsive MRI (Scheme 1). New 64Cu-labelled biocompatible phthalocyanines were efficiently synthetized with suitable non decay-corrected radiochemical yields (50-98%), which demonstrate high in vitro stability under physiological conditions (24h). Their in vivo PET biodistribution imaging will be also presented and discussed. In addition, the synthesis of new potential bi- and mono-modal redox responsive Mnporphyrin MRI probes is presented. Their Mn(III)/Mn(II) transformation in the presence of different biological reductants will be also discussed.

Scheme 1 Acknowledgements: The authors thank FCT-Portugal (Portuguese Foundation for Science and Technology) and FEDEREuropean Regional Development Fund Portugal, through the COMPETE Programme (OperationalProgramfor Competitiveness) for funding with UID/QUI/00313/2019 and POCI-01-0145-FEDER-027996. V.A.T. is grateful for her grant PD/BD/128318/2017, funded by FCT, Portugal. References: 1. a) S.M.A. Pinto, V.A. Tomé, M.J.F. Calvete, M.M.C.A. Castro, E.Tóth, C.F.G.C Geraldes, Coordin. Chem. Rev., 2019, 390, 1– 31.b) M.J.F. Calvete, S.M.A. Pinto, M.M. Pereira, C.F.G.C. Geraldes, Coordin. Chem. Rev., 2017, 333, 82–107. 2. M.J.F. Calvete, S.M.A. Pinto, A.J. Abrunhosa, M.M. Pereira, in: Advances in Medicine and Biology. Vol. 108, Chapter 10, pp 217-250, 2017, Nova Science Publishers, Inc, New York. 3. A.V.C. Simões, S.M.A. Pinto, M.J.F. Calvete, C.M.F. Gomes, N.C. Ferreira, M. Castelo-Branco, J. Llop, M.M. Pereira, A.J. Abrunhosa RSC Adv, 2015, 5, 99540-99546 4. S.M.A. Pinto, M.J.F. Calvete, M.E. Ghica, S. Soler, I. Gallardo, A. Pallier, M.B. Laranjo, A.M.S. Cardoso, M.M.C.A. Castro, C.M.A. Brett, M.M. Pereira, É.Tóth, C.F.G.C. Geraldes, Dalton Trans, 2019, 48, 3249-3262.

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Triggering the immune system to fight cancer – activation of NK cells with small organic molecules Pedro F. Pinheiroa,b, Gonçalo C. Justinoa, Joana P. Mirandab, M. Matilde Marquesa a Centro de Química Estrutural – Instituto Superior Técnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; biMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649003 Lisboa, Portugal Email: pedro.pinheiro@tecnico.ulisboa.pt

Natural killer (NK) cells provide rapid responses to viral-infected cells and play a critical role in tumor immunosurveillance by directly inducing the death of tumor cells. Instead of acting via antigen-specific receptors, lysis of tumor cells by NK cells is mediated by alternative receptors, including NKG2D, NKp44, NKp46 and NKp30. B7H6, a surface protein present on a broad panel of tumor cells, including lymphoma, melanoma and neuroblastoma, was identified as a ligand for the NKp30 receptor, namely through the structural elucidation of the NKp30-B7H6 complex. The comparison between the 3D structures of unbound and B7H6-bound NKp30 demonstrated marked conformational changes that may be a key-factor for the NK-response activation role of B7H6. Due to the difficulties in promoting the overexpression of the B7H6 marker in tumor cells, and the limited access to recombinant proteins and synthetic peptides, we set to design a family of small organic molecules (SOMs) capable of mimicking the effect of B7H6 on the NKp30 receptor. Using computational tools (namely AutoDock Vina) we designed a family of SOMs based on the structure of the NKp30 receptor. Synthetic, stability and overall binding score considerations were used to select a subfamily of ca. 15 compounds for synthesis. From these, 10 completely characterized entities were tested in an MS-based binding assay using the recombinant extracellular portion of the receptor, which led to the identification of one lead compound. Further refining of the lead structure, based on computational and synthetic approaches, was performed to improve the overall properties in terms of solubility, serum protein binding and stability. Primary cultures of human NK cells were used to probe the stimulation of NK cell responses by the lead compound. EC50 values below 0.2 µM were found in TNF-α, IFN-γ and Granzyme B release assays. Co-cultures of NK cells and the human tumor cell line HCT116 were used to determine the effect of the lead compound on the cytotoxicity of NK cells. NK cell cytotoxicity doubled upon treatment with 1.25 µM of lead compound, as compared to control incubations. An inhibition effect was observed for concentrations greater than 2.5 µM (Figure 1). 2 .5

f o ld d e a th

2 .0 1 .5 1 .0 0 .5

-2

-1

L O G [L e a d c o m p o u n d (µ M )]

Figure 1 – HCT116 cell death in co-culture with NK cells (E:T ratio = 2) and exposed to the lead compound. NK cells were isolated from three healthy donors (n=4 for each donor). An EC50 value of 146 nM and an IC50 value of 4.6 µM were found.

Our lead compound was proven effective in activating the cytotoxic activity of NK cells, as demonstrated by the cytokine release and the tumor cell death assays. Further work aims to derivatize our ligands with tumor-targeting molecules to increase the specificity of the NK cell cytotoxic response. Acknowledgements: The authors thank the Portuguese NMR Network – IST Node and the Portuguese Mass Spectrometry Network – IST Node for access to the facilities. This work was supported by grant LPCC/NRS – Terry Fox 2015-17 from Liga Portguesa Contra o Cancro, grant SFRH/BD/110945/2015 from Fundação para a Ciência e a Tecnologia (FCT), and projects SAICTPAC/0019/2015, PTDC/QUI-QAN/32242/2017 and UID/QUI/00100/2019, funded by national funds through FCT and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement.

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S,N-peptide functionalisation with ortho activated aldehydes Hélio Faustino,a Maria J. S. Silva,a Luís F. Veiros,b Pedro M. P. Góisa a

Research Institute for Medicines (iMed.ULisboa). Faculty of Pharmacy, Universidade de Lisboa. Lisbon (Portugal). b Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa Email: heliofaustino@ff.ulisboa.pt

In recent years several methods for facile and precise modification of peptides and proteins were disclosed and become a powerful strategy to study biological processes, to construct therapeutics and functional hybrid materials without the need for more specialized techniques.1 In this context, aldehydes are known to react selectively with N-terminal Cysteines to produce thaizolides at low pH and with slow kinetics. These conditions are typically incompatible with a wide range of biomolecules, that also requires dilute conditions, implying the use of high stoichiometric amounts (≥100) of one of the reagents.2 Our group and Gao demonstrate that the activation of aromatic aldehydes with a boronic acid at the ortho position enables the formation of thiazolidines at the N-terminal cysteine residue at low micro molar range.3 A reaction that is highly selective, fast and easily reversible, allowing interactive modification of terminal and in chain cysteines with different maleimides while keeping a tight control of stoichiometric amounts for the different maleimides.3a Herein we will also demonstrate that aromatic aldehydes equipped with an ester moiety at the ortho position react specifically with N-terminal Cysteines amongst a variety of other amino acid functionalities to produce thiazolidines at low micromolar range. The kinetics of the process, stability of the products and their applications will also be discussed.

Scheme 1: General scheme for the reaction of N-terminal Cysteines with ortho activated aldehydes. Acknowledgements: Support for this work was provided by FCT through PTDC/QEQ-QOR/1434/2014, PTDC/QUI-QOR/29967/2017, UID/DTP/04138/2013, SAICTPAC/0019/2015 and UID/DTP/04138/2019 (iMed.ULisboa). HF acknowledges financial support from SFRH/BPD/102296/2014. References: 1. O. Koniev and A. Wagner, Chem. Soc. Rev., 2015, 44, 5495. 2. a) L. Zhang, J. P. Tam, Anal. Biochem. 1996, 233, 87. b) G. J. L. Bernardes, M. Steiner, I. Hartmann, D. Neri, G. Casi, Nat. Protoc. 2013, 8, 2079. c) D. Bermejo-Velasco, G. N. Nawale, O. P. Oommen, J. Hilborn, O. P. Varghese, Chem. Commun. 2018, 54, 12507. 3. a) H. Faustino, M. J. S. A. S. A. Silva, L. F. Veiros, G. J. L. Bernardes, P. M. P. P. Gois, Chem. Sci. 2016, 7, 5052. b) A. Bandyopadhyay, S. Cambray, J. Gao, Chem. Sci. 2016, 7, 4589.

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Fighting breast cancer with ruthenium-based metallodrugs endowed with tumor-targeting vectors Leonor Côrte-Real,a Ana Rita Brás,a,b,c Ana Preto,b,c M. Helena Garcia,a Andreia Valentea a

Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749016, Lisboa, Portugal. b CBMA – Centre of Molecular and Environmental Biology, University of Minho, Braga, Portugal. c IBS-Institute of Science and Innovation for Bio-Sustainability, University of Minho, Braga, Portugal Email: ldcortereal@fc.ul.pt

Breast cancer is the most common and the second leading cause of death in women worldwide. Over the past two decades breast cancer mortality rates have declined, however, triple-negative breast cancer (TNBC - defined by the lack of expression of estrogen (ER), progesterone (PR) and HER2 receptors) continues to have a very poor prognosis and no effective treatment is currently available. Our group is exploring two different approaches to target TNBC: passive and active targeting. Thus, by using macromolecules and/or biomolecules in the design of new compounds an increase on the selectivity and efficiency is expected. Recent results regarding the possible targets and mechanism of action of two promising ‘Ruthenium-cyclopentadienyl’ compounds with the general formula [Ru(Cp)(PPh3)(bipy-R)]+, where R = biotin or polylactide will be shown and discussed1-3. These results encompass antiproliferative activities (assessment of cytotoxicity), cell death mechanisms, intracellular distributions (drug internalization), F-actin staining (cytoskeleton morphology changes) and anti-metastatic abilities (colony formation assay). Important results from the multidrug resistance (MDR) assay on cells overexpressing ABC transporters will also be disclosed, revealing exceptional and unprecedented properties. Finally, results from the toxicity assessment in a zebrafish model will also be presented.

Figure 1: Schematic representation of the targets of the new Ru compounds. Acknowledgements: This work was financed by the Portuguese Foundation for Science and Technology (FCT) - projects UID/QUI/00100/2019, PTDC/QUI-QIN/28662/2017, UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569) and UID/BIA/04050/2019. L. Côrte-Real and A.R. Brás thank FCT for their Ph.D. Grants (SFRH/BD/100515/2014 and SFRH/BD/139271/2018, respectively). A. Valente acknowledges the CEECIND 2017 Initiative (CEECIND/01974/2017) and the COST Action 17104 STRATAGEM (European Cooperation in Science and Technology). References: 1. L. Côrte-Real, B. Karas, P. Gírio, A. Moreno, F. Avecilla, F. Marques, B.T. Buckley, K.R. Cooper, C. Doherty, P. Falson, M.H. Garcia, A. Valente, Eur. Journ. Med. Chem. 2019, 163, 853. 2. L. Côrte-Real, B. Karas, A.R. Brás, A. Pilon, F. Avecilla, F. Marques, A. Preto, B.T. Buckley, K.R. Cooper, C. Doherty, M.H. Garcia, A. Valente, Inorg. Chem. 2019, 58, 9135. 3. T. Moreira, R. Francisco, E. Comsa, S. Duban-Deweer, V. Labas, A.P. Teixeira-Gomes, L. Combes-Soia, F. Marques, A. Matos, A. Favrelle, C. Rousseau, P. Zinck, P. Falson, M.H. Garcia, A. Preto, A. Valente, Eur. Journ. Med. Chem. 2019, 168, 373.

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Benzylaminobenziodoxolone – a new reagent for electrophilic amination Diogo L. Poeira, M. Manuel B. Marques LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica (Portugal) Email: d.poeira@campus.fct.unl.pt

The C-N bond is one of the most abundant bonds in organic compounds and has a great importance due to the diverse biological activities of nitrogen-containing compounds.1 The typical methods for the formation of C-N bonds exploit the nucleophilic properties of the nitrogen moiety, e.g.: nucleophilic substitution, reductive amination or metal-catalysed C-N cross-couplings such as the Buchwald-Hartwig amination.2 Inversion of polarity or umpolung reactivity is also possible, using an electrophilic nitrogen source such as chloramines. While this method has gained some recent attention,3,4 it is mostly limited to the use of transition metals3 or organometallic reagents.5 Iodine(III) compounds exhibit reactivity and chemical properties similar to those of transition metal complexes,6,7 and have recently been explored as electrophilic synthons of normally nucleophilic groups.8 Particularly, the iodine(III)-bearing cyclic benziodoxoles and benziodoxolones have attracted much interest in the scientific community due to their increased stability when compared to the acyclic analogues.9 In our investigation, we have reported the use of hypervalent iodine reagents for the transfer of sulfonyl groups to amines.10 In the sequence of this work we have developed a new benziodoxolone-based reagent for electrophilic amination. Herein the advancements in the C-N bond formation via umpolung reaction will be presented (Scheme 1).

Scheme 1 – Electrophilic amination of α-ketoesters with benzylaminobenziodoxolone. Acknowledgements: We thank the FC&T for the fellowship SFRH/BD/116322/2016. This work was supported by the Associate Laboratory for Green Chemistry- LAQV which is financed by national funds from FCT/MCTES (UID/QUI/50006/2019) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER - 007265). The National NMR Facility is supported by FC&T (ROTEIRO/0031/2013 – PINFRA/22161/2016, co-financed by FEDER through COMPETE 2020, POCI, and PORL and FC&T through PIDDAC). References: 1. J. Bariwal, E. Van der Eycken, Chem. Soc. Rev., 2013, 42, 9283. 2. P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev., 2016, 116, 12564. 3. M. Corpet, C. Gosmini, Synthesis, 2014, 46, 2258. 4. Z. Zhou, L. Kurti, Synlett, 2019, 30, 1525. 5. T. Hatakeyama, Y. Yoshimoto, S. K. Ghorai, M. Nakamura, Org. Lett., 2010, 12, 1516. 6. P. J. Stang, V. V. Zhdankin, Chem. Rev., 1996, 96, 1123. 7. M. S. Yusubov, V. V. Zhdankin, Curr. Org. Synth., 2012, 9, 247. 8. Y. F. Li, D. P. Hari, M. V. Vita, J. Waser, Angew. Chem.-Int. Ed., 2016, 55, 4436. 9. A. Yoshimura, V. V. Zhdankin, Chem. Rev., 2016, 116, 3328. 10. D. L. Poeira, J. Macara, H. Faustino, J. A. S. Coelho, P. M. P. Gois, M. M. B. Marques, Eur. J. Org. Chem., 2019, 15, 2695.

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Inhibition of pancreatic α-amylase activity by a group of hydroxyxanthones Clementina M. M. Santos,a-c Carina Proença,b Marisa Freitas,b Alberto N. Araújo,b Artur M. S. Silva,c Eduarda Fernandesb a

Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal. bLAQV-REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. cLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. Email: clems@ipb.pt

Diabetes mellitus is a non-infectious and non-transmissible life threatening disease. It is one of the fastest growing health challenges of the current century, in which the number of adults living with diabetes have more than tripled over the past 20 years. According to the International Diabetes Federation, 1 in 11 adults (20-79 years) have diabetes (463 million people) and 2 in 3 people with diabetes live in urban areas.1 This may be closely related to genetic and lifestyle factors such as physical inactivity, unhealthy diets, obesity, raised blood cholesterol and glucose, stress, etc.2 Diabetes mellitus is an endocrine disorder that occurs when pancreas does not produce enough insulin, when the body cannot use insulin efficiently or both situations, leading to chronic hyperglycemia. Thus, the control of postprandial blood glucose level via the inhibition of digestive enzymes, such as α-glucosidase and/or α-amylase, is a relevant strategy for the management of type 2 diabetes and its complications.3 During the last two decades, in the pursuit for novel antidiabetic drugs, a wide variety of natural and synthetic xanthone derivatives have been applied in the inhibition of α-glucosidase enzyme activity, however, the effects of this class of compounds on the activity of α-amylase enzyme is scarce.4 With this ratio in mind and as part of our on-going project, the aim of the present study is to investigate the effect of a series of hydroxyxanthones 1 on pancreatic α-amylase activity to find out the relevance of this group of compounds in controlling blood glucose levels for the treatment of disorders related with the carbohydrate uptake. Different concentrations of xanthones 1 were incubated with the enzyme and the hydrolysis of the substrate 2-chloro-p-nitrophenyl-α-D-maltotriose was monitored spectrophotometrically at 405 nm. Acarbose was used as the standard inhibitor. In addition, the study of the inhibition type was carried out through nonlinear regression Michaelis-Menton enzymatic kinetics and the corresponding Lineweaver-Burk plot.5 The results pointed out that the IC50 values obtained ranged from 23 to 90 μM, considerably higher than the values obtained for the positive control acarbose (IC50 = 0.62 ± 0.07 μM). For the active compounds, two of them revealed a competitive type of inhibition while for the remaining ones a noncompetitive type of inhibition was recorded. More details concerning the structureactivity relationship will be presented and discussed in this communication. Acknowledgements: This work received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007265) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/AGR/00690/2019; UID/QUI/50006/2019; UID/QUI/00062/2019, and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI-01-0145FEDER-029241), and under the framework of QREN (NORTE-01-0145-FEDER-000024).

References: 1. International Diabetes Federation. IDF Diabetes Atlas. In IDF Diabetes Atlas. 9th ed. 2019. Available from: https://www.diabetesatlas.org/en/. 2. H. Kolb, S. Martin, BMC Medicine 2017, 15, 131. 3. U. Ghani, Eur. J. Med Chem. 2015, 103, 133. 4. C. M. M. Santos, M. Freitas, E. Fernandes, Eur. J. Med. Chem. 2018, 157, 1460. 5. C. Proença, M. Freitas, D. Ribeiro, E. F. T. Oliveira, J. L. C. Sousa, S. M. Tomé, M. J. Ramos, A. M. S. Silva, P. A. Fernandes, E. Fernandes, J. Enz. Inhib. Med. Chem. 2019, 34, 577.

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Multi-component synthesis of novel 1,2,3-triazoledihydropyrimidinone hybrids: tackling cancer and Alzheimer’s disease Elisabete P. Carreiro,a Ana Sena,b José M. Padrón,c Óscar Lopez,d Anthony J. Burkea,b a Centro de Química de Évora & LAQV-Requimte, University of Évora, Institute for Research and Advanced Training (IIFA), Rua Romão Ramalho, 59, 7000-671 Évora, Portugal. bDepartment of Chemistry, University of Évora, School of Science and Technology, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal. cBioLab, Instituto Universitario de Bio-Orgánica “Antonio González”, Universidad de La Laguna, Apartado de correos 456, 38200 La Laguna, Islas Canarias, Spain. dDepartamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071, Seville, Spain Email: betepc@uevora.pt

At the moment, Cancer and Alzheimer's Disease are two very problematic illnesses. The numbers of patients are continuously increasing. To counteract this trend, the discovery of new innovative therapeutics has decreased the number of deaths over the last number of years. Over the last years there has been a growing interest in the discovery of new hybrid compounds that can act on several targets, such is the case with 1,2,3-triazoledihydropyrimidinone (DHPM) hybrids.1,2 We developed a novel family of 1,2,3-triazole-DHPM hybrids (Scheme 1) and evaluated their biological activity against several targets. This new family is divided in two types of hybrids: Hybrids A, containing the 1,2,3-triazole unit at C5-position of the DHPM (obtained by multicomponent Copper-Catalyzed-Alkyne-Azide Cycloaddition (CuAAC)Biginelli reactions) and Hybrids B, possessing two 1,2,3-triazole units attached at the C5 and C6 positions of the DHPM (assessed by multi-sequential reactions, that included: bromination, azidation and CuAAC.3 Some of these hybrids showed anti-proliferative activity against different cancer cell lines: A549 and SW1573 (non-small cell lung), HBL100 and T-47D (breast), HeLa (cervix), WiDr (colon); as well as demonstrating clear BuChE inhibitory activity. Moreover, these compounds show significant dual targeting characteristics. In this communication we will discuss our latest results. X

N N N

Multi-sequential reactions Ph

NH N H

X= H, Cl, OBn Y= H, Br, OMe

N N N

N H

N N

Hybrids A

NH N Br

O O

R Hybrids B

Biological Assays Antiproliferative Assays Againts Cancer cell lines

BuChE and AChE Inhibition Assays

Scheme 1. Synthesis of hybrids A and B for biological evaluation. Acknowledgements: We are grateful for funding from the Foundation for Science and Technology (FCT) Portugal via the Strategic Project UID/QUI/0619/2019 (attributed to CQE-UE) References: 1. (a). L. H. S Matos, F. T. Masson, L. A. Simeoni, M. Homem-de-Mello, Eur. J. Med Chem. 2018, 143, 1779. (b) D. Dheer, V. Singh, R. Shankar, Bioorg. Chem. 2017, 71, 30. 2. M. Teleb, O. H. Rizka, F.-X. Zhangc, F. R. Fronczekd, G. W. Zamponic , H. Fahmye, Bioorganic Chemistry, 2018, 83, 354. 3. E. P. Carreiro, A. Sena, A. J. Burke, A.J. Synlett, 2019, paper accepted.

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iLiquids4Malaria: from ILs to SAILs – an insight Ana Teresa Silvaa, Joana Gomesa, Cátia Teixeiraa, Cristina Prudênciob,c, Eduardo F. Marques,d Isabel Oliveira,d Fátima Nogueirae,Inês Moraise, Miguel Prudênciof , Diana Fontinhaf, Paula Gomesa, Ricardo Ferraza,b aLAQV-REQUIMTE,

Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto; bCiências Químicas

e das Biomoléculas, CISA, Escola Superior de Tecnologia da Saúde do Porto – Instituto Politécnico do Porto; cI3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, d Univ Porto, Dept Chem & Biochem, CIQUP, Fac Sci, eGlobal Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, fInstituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Av.Prof. Egas Moniz, 1649-028 Lisboa, Portugal

Email: ricardoferraz@eu.ipp.pt

Since the 1990s, ionic liquids (ILs) have been a focus of increasing interest for Science and Technology. Over the past decade, the potential applications of ILs in the Life and Health Sciences have attracted enormous attention, not only concerning their use as excipients in new formulations, but also regarding the creation of ILs derived from active pharmaceutical ingredients (API-ILs) that constitute new therapeutic entities per se. With this innovative project, we have pursued the synthesis, evaluation of in vitro antiplasmodial activity, and tensioactivity of novel API-ILs produced by acid-base neutralization of antiplasmodial amines such as chloroquine and primaquine with natural fatty acids (FA). This approach was designed to deliver API-IL that behave as Surface-Active Ionic Liquids (SAILs), whose expected selfaggregation properties might allow them to simultaneously exhibit therapeutic activity and act as their own carriers for enhanced intracellular delivery. In parallel, we have also produced the corresponding covalent (amide) analogs, via addition-elimination (condensation) reactions using standard in situ peptide coupling procedures, enabling a comparative study of both the ionic and covalent conjugates. The use of low-cost strategies, like the one disclosed herein, towards the rescuing of classical drugs that are losing efficacy is of utmost importance to tackle diseases that are endemic to low-to-medium-income countries. In this communication will detail the encouraging findings made thus far in this regard.

Scheme 1. From Ionic Liquids to Surface-Active Ionic Liquids. Acknowledgements: Thanks are due to Fundação para a Ciências e Tecnologia (FCT), Portugal, through projects UID/QUI/50006/2019, and PTDC/BTM-SAL/29786/2017 and also to NORTE-01-0145-FEDER-024156, supported by NORTE 2020, under the PORTUGAL 2020 Partnership Agreement, through the ERDF and by FCT.

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Sustainable synthesis of biologically important furan derivatives Ana C. Fernandes, Carolina A. Carreira, João A. T. Caetano, Vera M. S. Isca Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. Email: anacristinafernandes@tecnico.ulisboa.pt

The development of sustainable and green processes for the synthesis of pharmaceutical substances continues to be one of the main challenges of the pharmaceutical industry. Direct connection of the drug center to biomass resources provides an efficient and ecological approach for the sustainable long term production of pharmaceutical substances. For example, the furan ring skeleton is present in numerous drugs possessing a variety of biological activities such as antimicrobial, anti-inflammatory, antitubercular, antitumor, anti-HIV, antimalarial, antiviral, antifugal.1 For these reasons, the development of new methodologies for the sustainable synthesis of furan derivatives is highly desirable. Among biomass resources, carbohydrates form by far the largest natural source of carbon and are considered the ideal feedstock for the production of platform of valueadded compounds. In this communication, we will present the one-pot conversion of carbohydrates into a variety of biologically important furan derivatives with moderate to good overall yields (Figure 1).2-4

Biomass resources

Figure 1 – Conversion of carbohydrates into biologically important furan derivatives. Acknowledgements: The authors thank the project UID/QUI/00100/2019 and the Portuguese NMR Network (IST–UTL Center) for providing access to the NMR facilities. ACF (IF/00849/2012) acknowledges FCT for the “Investigador FCT” Program. References: 1. R. Banerjee, K. HKS, M. Banerjee, Int. J. Rev. Life. Sci. 2012, 2, 7. 2. J. A. T. Caetano, A. C. Fernandes, Green Chem. 2018, 20, 2494. 3. V. M. S. Isca, A. C. Fernandes, Green Chem. 2018, 20, 3242. 4. J. R. Bernardo, M. C. Oliveira, A. C. Fernandes, Mol. Catal. 2019, 465, 87.

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Photodynamic inactivation of Escherichia coli using neutral and cationic porphyrins Sara R. D. Gamelas,a Joana M. D. Calmeiro,a Ana T. P. C. Gomes,b Maria A. F. Faustino,a Maria G. P. M. S. Neves,a Adelaide Almeida,b Augusto C. Tomé,a João P. C. Tomé,c Leandro M. O. Lourençoa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. bCESAM and Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal. cCQE e Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal. Email: sara.gamelas@ua.pt

Photodynamic inactivation (PDI) is a therapeutic process that requires the photoactivation, by visible light, of a photosensitizer (PS), which in presence of oxygen leads to the formation of cytotoxic reactive oxygen species (ROS) that can cause lethal oxidative damage in microbial targets.1-5 An example of these PSs are the porphyrinic dyes and analogues, which present unique photochemical and photophysical properties against microorganisms, including multi-resistant bacteria.3-6 In this communication, it will be reported and discussed the synthesis and characterization of the neutral (1, 1a, 2, 2a) and cationic (1b, 1c, 2b, 2c) porphyrin derivatives presented in Figure 1. The photodynamic efficiencies of these derivatives against the Gram-negative bioluminescent Escherichia coli bacterium will be also analysed. F

F F

R F

N N

N F

F F

1, 2, M = 2H 1a, 2a, M = Zn

F R

1, 1a

1b, 1c

2, 2a

2b, 2c

4 I-

F F

R F

F R

F F

F 1b, 2b, M = 2H

2 SO42-

1c, 2c, M = Zn

Figure 1: Structure of the porphyrin derivatives. Acknowledgements: Thanks are due to FCT for the financial support to QOPNA (UID/QUI/00062/2019), LAQV-REQUIMTE (UIDB/50006/2020), CESAM (FCT UID/AMB/50017/2019) and CQE (FCT UID/QUI/0100/2019) research units, and FCT projects P2020-PTDC/QUI-QOR/31770/2017 and P2020PTDC/QEQ-SUP/5355/2014, through national funds (PIDDAC) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and Internationalization-COMPETE 2020, within the PT2020 Partnership Agreement. S. G. and J. C. thank FCT for the research fellow SFRH/BD/143549/2019 and BI/UI51/7955/2019, respectively. References 1. M. C. Gomes, S. M. Woranovicz-Barreira, M. A. F. Faustino, R. Fernandes, M. G. P. M. S. Neves, A. C. Tomé, N. C. M. Gomes, A. Almeida, J. A. S. Cavaleiro, Â. Cunha, J. P. C. Tomé, Photochem. Photobiol. Sci., 2011, 10, 1735. 2. E. Alves, M. A. F. Faustino, M. G. P. M. S. Neves, Â. Cunha, H. Nadais, A. Almeida, J. Photochem. Photobiol. C, 2015, 22, 34. 3. D. C. S. Costa, M. C. Gomes, M. A. F. Faustino, M. G. P. M. S. Neves, A. Cunha, J. A. S. Cavaleiro, A. Almeida, J. P. C. Tomé, Photochem. Photobiol. Sci, 2012, 11, 1905. 4. D. C. S. Costa, V. F. Pais, A. M. S. Silva, J. A. S. Cavaleiro, U. Pischel, J. P. C. Tomé, Tetrahedron Lett. 2014, 55, 4156. 5. L. M. O. Lourenço, A. Sousa, M. C. Gomes, M. A. F. Faustino, A. Almeida, A. Almeida, A. M. S. Silva, M. G. P. M. S. Neves, J. A. S. Cavaleiro, Â. Cunha, J. P. C. Tomé, Photochem. Photobiol. Sci., 2015, 10, 1853. 6. E. Alves, J. M. M. Rodrigues, M. A. F. Faustino, M. G. P. M. S. Neves, J. A. S. Cavaleiro, Z. Lin, Â. Cunha, M. H. Nadais, J. P. C. Tomé, A. Almeida, Dyes. Pigments., 2014, 110, 80.

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Asymmetric Neber approach to chiral 2-(tetrazol-5-yl)-2H-azirines Cláudia C. Alves,a Carla Grosso,a Ana L. Cardoso,a Pedro C. Barrulas,b Anthony Burke,b Américo Lemos,a,c Teresa M. V. D. Pinho e Meloa a

CQC and Department of Chemistry, University of Coimbra; 3004-535 Coimbra, Portugal; bCentro de Química de Évora and Department of Chemistry, University of Évora, 7000 Évora, Portugal; cFCT, University of Algarve, Campus Gambelas, 8005-139 Faro, Portugal. Email: claudialves2094@gmail.com

The unique features of 2H-azirines, such as their high ring-strain, the activated iminic bond or their N-lone pair, make them highly reactive and versatile molecules being used in the synthesis of numerous nitrogen-containing compounds. The discovery of naturally occurring biologically active compounds such as azirinomycin, (-)-dysidazirine and motualevic acid F, which contain chiral 2H-azirine-2-carboxylates in their structure, led to an increasing interest in the development of asymmetric synthetic methodologies towards this class of compounds.2 Our group recently described the Neber approach to 2-(tetrazol-5-yl)-2H-azirines, bioisosteres of the 2H-azirine-carboxylates.3 As a continuation of this work, the asymmetric version of this synthetic route to 2-(tetrazol-5-yl)-2H-azirines, resorting to organocatalysis, was developed. Therefore, a variety of different organocatalysts and reaction conditions were tested in order to optimize the enantioselectivity of this transformation. Moreover, new 6β-aminopenicillanic acid derived thiourea catalysts 3 were synthesized and tested in the reaction of β-ketoxime-1H-tetrazoles 1 bearing different substituents at the C3 position. The desired chiral products 5, with R configuration, were obtained in moderate yields and moderate to excellent enantioselectivities (up to > 99%) (Scheme 1).3 Further details of this study will be disclosed in this communication.

Scheme 1: One-pot asymmetric Neber reaction of β-ketoximes catalyzed by 6-APA derived thioureas. Acknowledgements: Coimbra Chemistry Center (CQC) is supported by the Portuguese Agency for Scientific Research, Fundação para a Ciência e a Tecnologia (FCT) through project UID/QUI/00313/2019 co-funded by COMPETE2020-UE. CG and CCA acknowledges FCT for their PhD research grants (SFRH/BD/130198/2017 and PD/BD/143159/2019). We also acknowledge the UC-NMR facility for the NMR spectroscopic data. References: 1. Khlebnikov A. F.; Novikov S. M.; Rostovskii, N. V. Tetrahedron 2019, 2555. 2. a) Miller T. W.; Tristram, E. W.; Wolf F. J. Antibiot. 1971, 48. b) Molinski T. F.; Ireland C. M. J. Org. Chem. 1988, 53, 2103. 3. a) Cardoso A. L.; Gimeno, L.; Lemos A.; Palacios, F.; Pinho e Melo T. M. V. D. J. Org. Chem. 2013, 78, 6983. b) Alves, C. Asymmetric Neber Reaction in the Synthesis of 2-(Tetrazol-5-yl)-2H-Azirines. MSc, Universidade de Coimbra, 2018.

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A sustainable aproach for the discovery of medicinal relevant scaffolds: from furans to cyclopentenones Rafael F. A. Gomes,a Kessia Andrade,a Vera Isca, Patrícia Rijo,a,b Jaime A. S. Coelho,a Carlos A. M. Afonsoa a

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649- 003, Lisboa, Portugal, bCBIOS - Research Center for Health Sciences & Technologies, ULusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal Email: rafael.gomes@campus.ul.pt

Medicinal relevant small molecules derived from biomass is a field of interest due to 1) structural diversity obtained via biomass modification, 2) sustainable and environmentally friendly approach, 3) low cost of starting materials most likely lead to economic benefits. Our group has been involved in the development of methodologies for the preparation of biomass derivatives, such as 5-hydroxymethylfurfural1a (HMF), and subsequent transformation to biologically active scaffolds such as anticancer triarylmethanes.1b On the other hand, our group recently developed methodologies for the preparation of cyclopentenones both from HMF2 and from furfural,3 another biomass derivative with industrial scale preparation from lignocellulosic material. In this work we show the potential of different cyclopentenone families as scaffolds with anticancer and antimicrobial activity.4 We discuss structure activity relationship and stability of the said compounds, and prepare derivatives that mask their inherent characteristic of being Michael-acceptors, therefore reducing the probability of poor pharmacokinetic properties and toxicity (Scheme 1).

Scheme 1: Selected example of cyclopentenone families prepared from furans. Acknowledgements: We thank Fundação para a Ciência e a Tecnologia (FCT) (ref. PD/BD/128316/2017; UID/DTP/04138/2013, PTDC/QUI-QOR/32008/2017) and COMPETE Programme (SAICTPAC/0019/2015) for financial support. References: 1. a) Rafael F. A. Gomes, Yavor N. Mitrev, Svilen P. Simeonov, Carlos A. M. Afonso, ChemSusChem – VIP paper, 2018, 11 (10), pp 1612-1616. b) Rafael F. A. Gomes, Jaime A. S. Coelho, Raquel F. M. Frade, Alexandre F. Trindade, Carlos A. M. Afonso, J. Org. Chem., 2015, 80 (20), pp 10404–10411. 2. Rafael F. A. Gomes, Jaime A. S. Coelho, Carlos A. M. Afonso, ChemSusChem – VIP paper, 2019, 12, pp 420-425. 3. Rafael F. A. Gomes, Nuno R. Esteves, Jaime A. S. Coelho, Carlos A. M. Afonso, J. Org. Chem., 2018, 83 , pp 7509-7513. 4. Manuscript submited

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Expeditious synthesis of chiral sulfones via umpolung reaction João Macara, M. Manuel B. Marques LAQV-REQUIMTE, Departamento de Química Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa Campus de Caparica, 2829-516 Caparica, Portugal Email: j.macara@campus.fct.unl.pt

The sulfone moiety is animportant functional group in organic synthesis, with a wide applications in the field of pharmaceutical, agrochemical and material industry.1 The sulfone group can be used as a temporary modulator of chemical reactivity, resulting in an important synthetic intermediate of several product classes, such as oxazoles or imidazoles.2 Sulfone groups can act as an activating, electro-withdrawing substituent in Michael acceptors, or as a good leaving group or even stabilize adjacent carbanions.3 The large demand for sulfones creates the necessity for a continuous research for more efficient, robust and sustainable synthetic routes. Classic methods to prepare sulfones rely on the oxidation of sulfides or sulfoxides, alkylation of sulfinate salts or Friedel-Drafts-type sulfonylation.1 These methods suffer from poor regioselectivity, functional group incompatibility or harsh conditions. The more recent strategies rely on the use of transition-metal-catalyzed coupling reactions of sodium sulfinates, direct addition of sulfonyl-type radicals to alkene and alkynes or the use of SO2-surrogates. The inherent difficulties of these methods are the need of pre-funcionalized starting materials, poor regioselectivity or the generation of large amounts of unwanted byproducts.4 Additionally, although there is a great deal of methods to generate β-chiral sulfones, the generation of α-chiral sulfones in not so explored. Our group developed a novel methodology for the transfer of the sulfonyl group to amines mediated by hypervalent iodine reagents, consisting on a versatile method of sulfonamide synthesis.5 Recently, we have investigated the synthesis of sulfones by sulfonyl group transfer to ketones and analogues. The use of hypervalent iodine compounds as functional groups transfer reagents is an emerging topic in organic chemistry. Moreover, the transfer of functional groups through an umpolung reaction has attracted considerable attention from the scientific community.6 Herein, we will present the last results on this simple and versatile route towards chiral and achiral sufones mediated by hypervalent iodine reagents.7

Scheme 1: Sulfone synthesis methodology. Acknowledgements: We thank to the FC&T for fellowships PD/BD/142864/2018 This work was supported by the Associate Laboratory for Green Chemistry- LAQV which is financed by national funds from FCT/ MCTES (UID/QUI/50006/2019) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER - 007265). The National NMR Facility is supported by FC&T (ROTEIRO/0031/2013 – PINFRA/22161/2016, co-financed by FEDER through COMPETE 2020, POCI, and PORL and FC&T through PIDDAC).

References: 1.Liu, N. W.; Liang, S.; Manolikakes, G., Recent Advances in the Synthesis of Sulfones. Synthesis-Stuttgart 2016, 48 (13), 1939-1973. 2.Li, J. J., Name Reactions in Heterocyclic Chemistry. Wiley: 2011. 3.Simpkins, N. S., THE CHEMISTRY OF VINYL SULFONES. Tetrahedron 1990, 46 (20), 6951-6984. 4.Liu, J. D.; Zheng, L. Y., Recent Advances in Transition-Metal-Mediated Chelation- Assisted Sulfonylation of Unactivated C-H Bonds. Advanced Synthesis & Catalysis 2019, 361 (8), 1710-1732. 5.Poeira, D. L.; Macara, J.; Faustino, H.; Coelho, J. A. S.; Gois, P. M. P.; Marques, M. M. B., Hypervalent Iodine Mediated Sulfonamide Synthesis. European Journal of Organic Chemistry 2019, (15), 2695-2701. 6.Charpentier, J.; Fruh, N.; Togni, A., Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chemical Reviews 2015, 115 (2), 650-682. 7.Macara, J.; Manuel B. Marques, M., Sumitted. 2019.

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Platinum(II) ring-fused chlorin photosensitizers for cancer theranostic applications: synthesis, in vitro cell biology and in vivo proof of concept Bruno F. O. Nascimento,a Mafalda Laranjo,b,c Márcia Campos,a,b Nelson A. M. Pereira,a Ana F. Brito,b,c Gonçalo Brites,b,c Marta Pineiro,a Maria Filomena Botelho,b,c Teresa M. V. D. Pinho e Meloa a

CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal. b Biophysics Institute and Institute for Clinical and Biomedical Research (iCBR), area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3004548 Coimbra. c CNC.IBILI Consortium, University of Coimbra, 3004-548 Coimbra, Portugal. Email: nascimento@ci.uc.pt

Photodynamic therapy (PDT) is a minimally invasive strategy for clinically treating many cancerous conditions and pre-malignant lesions in animals and human beings.1a The combination of a tumor-selective photosensitizer (PS), molecular oxygen and targeted illumination produces highly cytotoxic reactive oxygen species (ROS) directly within the tumor cells. Moreover, PDT can damage the tumor-associated vasculature, causing local inflammatory processes that may trigger a subsequent immune reply.1b Unlike surgery or chemo/radiotherapy, the adjacent extracellular matrix is usually unaffected by PDT and, thus, tissue healing is improved with scaring hardly being noticeable.1a Since PSs are typically fluorescent dyes that selectively buildup in tumor tissues, they can also be used to visualize and differentiate tumor cells from normal tissue, thus refining the accuracy of tumor resection procedures, and act as useful theranostic (THERApy + diagNOSTIC) agents.1b,c Our group recently reported on near-infrared (NIR) luminescent Pt(II) 4,5,6,7-tetrahydropyrazolo[1,5a]pyridine-fused chlorins that display great photostability, high photocytotoxicity, and interesting simultaneous fluorescence and phosphorescence emission properties, demonstrating vast potential as PSs for skin malignant melanoma and also as interesting ratiometric oxygen probes in chemical and biological media.2 Herein, we describe the synthesis of some closely related Pt(II) chlorin derivatives (Figure 1-I), comprising both electron withdrawing and electron donating groups at the molecules’ periphery (R1), as well as functionalities of different polarity at the exocyclic fused ring (R2). Results of the in vitro cell biology studies in human A375 skin malignant melanoma, OE19 esophageal adenocarcinoma and HT1376 urinary bladder carcinoma cell lines will be disclosed. Proof of concept for fluorescence imaging diagnostic and photodynamic treatment with the lead PS of the series, using a standard in vivo A375 melanoma/mouse model (Figure 1-II), will also be presented. I

Figure 1: I. Pt(II) ring-fused chlorins synthesized and evaluated in the present work. II. Fluorescence images of nude mice bearing A375 skin malignant melanoma tumors in the armpits, without (A) and with (B) PS injection (λexc = 605 nm and λem = 695-770 nm). Acknowledgements: financial aid from the Portuguese Foundation for Science and Technology (FCT), co-funded by the European Regional Development Fund (FEDER) through PT 2020/CENTRO 2020 (CENTRO-01-0145-FEDER000014/MATIS), and CIMAGO is appreciated. The Coimbra Chemistry Center (CQC) is supported by project UID/QUI/00313/2019. The CNC.IBILI Consortium is supported via projects PEst-UID/NEU/04539/2013, UID/NEU/04539/2019 and POCI-01-0145-FEDER-007440. References: 1. a) J. Dobson, G. F. de Queiroz, J. P. Golding, Vet. J. 2018, 233, 8. b) D. van Straten, V. Mashayekhi, H. S. de Bruijn, S. Oliveira, D. J. Robinson, Cancers 2017, 9, 19. c) J. Sandland, N. Malatesti, R. Boyle, Photodiag. Photodyn. Ther. 2018, 23, 281. 2. a) N. A. M. Pereira, M. Laranjo, J. Casalta-Lopes, A. C. Serra, M. Pineiro, J. Pina, J. S. Seixas de Melo, M. O. Senge, M. F. Botelho, L. Martelo, H. D. Burrows, T. M. V. D. Pinho e Melo, ACS Med. Chem. Lett. 2017, 8, 310. b) Platinum(II) ringfused chlorins, methods and uses thereof; Publication No: WO/2017/145092; Publication Date: 31.08.2017; Inventors: H. D. Burrows, T. M. V. D. Pinho e Melo, A. C. Serra, N. A. M. Pereira, L. Martelo, M. Pineiro, J. S. Seixas de Melo, J. Pina, M. F. Botelho, A. M. Abrantes, M. Laranjo; Applicant: Universidade de Coimbra.

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A novel route to the synthesis of xanthones by carbonylative Suzuki coupling Daniela R. P. Loureiro,a,b,c José X. Soares,c Ana Maia,a Sara Cunha,d Carlos M. G. Azevedo,a Salette Reis,c Carlos M. M. Afonso,a,b* Madalena M. M. Pinto,a,b a

Department of Chemical Sciences, Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal; bCentro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Matosinhos, Portugal; cLAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal; dLAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Bromatology and Hydrology, Faculty of Pharmacy, University of Porto, Porto, Portugal

Email: cafonso@ff.up.pt

Xanthones are considered privileged structures in Medicinal Chemistry since, depending on their substitution patterns, they are useful ligands for more than one type of receptor or enzyme target.1 Therefore, xanthone derivatives show several biological activities, such as antimicrobial, antitumor, anti-inflammatory, among others.1,2 Consequently, new and improved synthetic routes to xanthones bearing different substitution patterns is an important research topic. The most common methodologies for the synthesis of xanthone derivatives rely on a benzophenone intermediate, which is then cyclized into the xanthone scaffold.3 However, the harsh experimental conditions and the structural requirements of the building blocks hampers the application of these methods. Recently, new suitable alternatives for synthesizing benzophenones have been emerged based on palladiumcatalyzed carbonylative Suzuki coupling reactions.4,5 In this work, a design of experiments was implemented to optimize the synthesis of xanthones by carbonylative Suzuki coupling.6 Iodophenol (1) and (2methoxyphenyl)boronic acid (2) were used as building blocks to provide in a single reaction step the xanthone (3) (Scheme 1). Five Pd-based catalysts were evaluated, and the best catalyst, a Pd-pincer complex, was selected. Other reaction parameters were then evaluated, namely the number of equivalents of the base and the catalyst, and the percentage of water in the reaction. The best conditions were selected and used to synthesize the 9H-xanthen-9-one. Based on these results, new xanthone derivatives were one-step prepared using this synthetic route.

Scheme 1: One step synthesis of the xanthone by a carbonylative Suzuki coupling reaction. Acknowledgements: This research was partially supported by the Strategic Funding UID/Multi/04423/2019 through national funds provided by FCT – Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020 and the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER028736) through national funds provided by FCT – Foundation for Science and Technology and European Regional Development Fund (ERDF), through the COMPETE – Programa Operacional Factores de Competitividade (POFC) programme in the framework of the programme PT2020. Daniela R. P. Loureiro thanks FCT for her PhD grant (SFRH/BD/140844/2018). References: 1. Sousa, M.; Pinto, M., Synthesis of xanthones: an overview. Curr. Med. Chem. 2005, 12 (21), 2447-2479. 2. Pinto, M. M. M.; Castanheiro, R. A. P.; Kijjoa, A., Xanthones from Marine-Derived Microorganisms: Isolation, Structure Elucidation and Biological Activities. In Encyclopedia of Analytical Chemistry, John Wiley & Sons, Ltd: 2014. 3. Azevedo, C.; Afonso, C.; Pinto, M., Routes to xanthones: an update on the synthetic approaches. Curr. Org. Chem. 2012, 16 (23), 2818-2867. 4. Gautam, P.; Tiwari, N. J.; Bhanage, B. M., Aminophosphine Palladium Pincer-Catalyzed Carbonylative Sonogashira and Suzuki–Miyaura Cross-Coupling with High Catalytic Turnovers. ACS Omega 2019, 4 (1), 1560-1574. 5. Qi, X.; Jiang, L. B.; Li, H. P.; Wu, X. F., A Convenient Palladium-Catalyzed Carbonylative Suzuki Coupling of Aryl Halides with Formic Acid as the Carbon Monoxide Source. Chemistry – A European Journal 2015, 21 (49), 17650-17656. 6. Lundstedt, T.; Seifert, E.; Abramo, L.; Thelin, B.; Nyström, Å.; Pettersen, J.; Bergman, R., Experimental design and optimization. Chemometr. Intell. Lab. 1997, 42, 3-40.

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Active pharmaceutical ionic liquids as a new platform for tuberculosis L. C. Branco,a D. Silva,a F. Santos,a M. M. Santos,a S. Gago,a Z. Petrovski,a A. R. Duarte,a R. Shroderb a LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica (Portugal). bInstituto de Química – Universidade Federal do Rio de Janeiro, Avenida Athos da Silveira Ramos, nº 149, Bloco A, 21941-909 Rio Janeiro, Brazil

Email: l.branco@fct.unl.pt

Tuberculosis (TB) is caused by infection with the slow-growing Mycobacterium tuberculosis (MT); currently causes 1.4 million deaths every year as well as 8 to 10 million new infections have been detected.1 Despite enormous efforts in the discovery of novel drugs, tuberculosis (TB) remains the first bacterial cause of mortality worldwide. The World Health Organization (WHO) has estimated that one-third of the total world population is latently infected with bacilli of MT (an estimated 2 billion people). The Control of the global TB epidemic has been impaired by the lack of an effective vaccine, by the emergence of drug-resistant forms of M. tuberculosis, and by the lack of sensitive and rapid diagnostics.2 In this context, novel active pharmaceutical drugs based ionic liquids (APIs-ILs) have been developed in order to improve the drug performance in terms of its stability, solubility, permeability and delivery.3 Recent achievements of our research team allowed the development of sustainable synthetic methodologies for combination of pharmaceutical drugs such as beta-lactams antibiotics (ampicillin, meropenem), fluoroquinolone antibiotics (ciprofloxacin and norfloxacin) and other drugs (mefloquine, ibuprofen) as cations or anions with adequate biocompatible counter-ions.4-6 The selection of counter-ions is important to improve the bioavailability, delivery, stability and therapeutic properties of the original TB drugs (scheme 1). The use of amphiphilic and hydrophobic as well as more polar counter-ions elucidate the cation-anion interactions and drug delivery. Herein, the different approaches using active pharmaceutical ILs as new platform for treatment of Tuberculosis will be presented.

Active Pharmaceutical Ionic Liquids as new platform for Tuberculosis Cation

X-

Y+ Anion

Mefloquine

X-; Y+ = Biocompatible Counter-ions

Meropenem

Scheme 1: Active Pharmaceutical ILs based on Mefloquine and Meropenem for Tuberculosis Acknowledgements: This work was supported by the Associate Laboratory for Green Chemistry- LAQV which is financed by national funds from FCT/MCTES (UID/QUI/50006/2019) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER - 007265). The National NMR Facility is supported by FC&T (ROTEIRO/0031/2013 – PINFRA/22161/2016, co-financed by FEDER through COMPETE 2020, POCI, and PORL and FC&T through PIDDAC). The authors thank the financial support by FCT – MCTES (PTDC/QUI-QOR/32406/2017; MAR2020 (MAR02.01.01-FEAMP0042; INOVA4AQUA project) and Solchemar company. References: 1. A. Zumla, P. Nahid, S.T. Cole, Nat. Rev. 2013, 12, 388e404 2. C. Lange, K. Dheda, D. Chesov, A. M. Mandalakas, Z. Udwadia, C R. Horsburgh, The Lancet 2019, 394, 10202. 3. I. M. Marrucho, L. C. Branco, L. P. N. Rebelo, Annual Rev. Chem. Biom. Eng. 2014, 5, 527. 4. a) R. Ferraz, V. Teixeira, D. Rodrigues, R. Fernandes, C. Prudêncio, J. P. Noronha, Z. Petrovski, L. C. Branco, RSC Adv. 2014, 4, 4301. b) C. Florindo, A. Costa, C. Matos, S. L. Nunes, A. N. Matias, C. M.M. Duarte, L. P. N. Rebelo, L. C. Branco, I. M. Marrucho, Int. J. Pharmaceutics 2014, 469, 179. 5. a) M. M. Santos L. R. Raposo G. V. S. M. Carrera, A. Costa, M. Dionísio P. V. Baptista, A. R. Fernandes, L. C. Branco, ChemMedChem, 2019, 14, 907. b) I. C. B. Martins, M. C. Oliveira, H. P. Diogo, L. C. Branco, M. T. Duarte, ChemSusChem 2017, 10, 1360. 6. a) S. Teixeira, M. M. Santos, R. Ferraz, C. Prudêncio, M. H. Fernandes, J. Costa-Rodrigues, L. C. Branco, ChemMedChem, 2019, 14, 1617. b) G. V. S. M. Carrera, M. M. Santos, A. Costa, I. Marrucho, M. N. da Ponte, L. C. Branco, New J. Chem 2017, 41, 6986.

OC29

Versatile phthalocyanine dyes as ‘therapeutic window’ for photoinactivation of microorganisms Cláudia P. S. Ribeiro, Joana M. D. Calmeiro, Sara R. D. Gamelas, Leandro M. O. Lourenço LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. Email: leandrolourenco@ua.pt

Photodynamic inactivation (PDI) is a therapeutic methodology that involves the photoactivation of a photosensitizer (PS) by visible light that in contact with molecular oxygen allow the formation of cytotoxic reactive oxygen species (ROS), which can cause lethal oxidative damage in microbial targets and their consequent destruction.1-5 phthalocyanine (Pc) dyes, which present exceptional photochemical and photophysical properties, has been shown as promising PSs against microorganisms.1-3 For that reason, the research for more selective and efficient PSs is a very hot topic area, including the design and preparation of novel Pc structures (Figure 1). In this context, it will be mentioned and discussed the synthesis of several cationic water-soluble Pc derivatives and their spectroscopic characterization. It will be also highlighted the most relevant biological results against Gram-negative bacteria (e.g. E. coli).

Figure 1: Structure of cationic zinc(II) phthalocyanine derivatives.

Acknowledgements: Support for this work was provided by FCT/MEC to QOPNA research unit (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020), and to the projects P2020-PTDC/QUIQOR/31770/2017 and P2020-PTDC/QEQ-SUP/5355/2014, through national founds (PIDDAC) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and Internationalization-COMPETE 2020, within the PT2020 Partnership Agreement. References: 1. L. M. O. Lourenço, D. M. G. C. Rocha, C. I. V. Ramos, M. C. Gomes, A. Almeida, M. A. F. Faustino, F. A. A. Paz, M. G. P. M. S. Neves, Â. Cunha, J. P. C. Tomé, ChemPhotoChem, 2019, 3, 1. 2. L. Marciel, L. Teles, B. Moreira, M. Pacheco, L. M. O. Lourenço, M. G. P. M. S. Neves, J. P. C. Tomé, A. Faustino, A. Almeida, Future Med. Chem., 2017, 9, 365. 3. L. M. O. Lourenço, A. Sousa, M. C. Gomes, M. A. F. Faustino, A. Almeida, A. Almeida, A. M. S. Silva, M. G. P. M. S. Neves, J. A. S. Cavaleiro, Â. Cunha, J. P. C. Tomé, Photochem. Photobiol. Sci., 2015, 10, 1853. 4. L. M. O. Lourenço, M. G. P. M. S. Neves, J. A. S. Cavaleiro, J. P. C. Tomé, Tetrahedron, 2014, 70, 2681. 5. a) J. M. D. Calmeiro, C. J. Dias, C. I. V. Ramos, A. Almeida, J. P. C. Tomé, M. A. F. Faustino, L. M. O. Lourenço, Dyes Pigm., 2019, DOI: https://doi.org/10.1016/j.dyepig.2019.03.021. b) J. T. Ferreira, J. Pina, C. A. F. Ribeiro, R. Fernandes, J. P. C. Tomé, M. S. Rodríguez-Morgade, T. Torres, J. Mater. Chem. B 2017, 5, 5862. c) J. T. Ferreira, J. Pina, C. A. F. Ribeiro, R. Fernandes, J. P. C. Tomé, M. S. Rodríguez-Morgade, T. Torres, ChemPhotoChem 2018, 2, 640. c) L. M. O. Lourenço, P. M. R. Pereira, E. Maciel, M. Válega, F. M. J. Domingues, M. R. M. Domingues, M. G. P. M. S. Neves, J. A. S. Cavaleiro, R. Fernandes, J. P. C. Tomé, ChemComm. 2014, 50, 8363.

OC30

Chalcones modulate the production of reactive species and NETs release by human neutrophils in normal and hyperglycemic conditions Adelaide Sousa,a Daniela Ribeiro,a Catarina M. Correia,b Vera L. M. Silva,b Artur M. S. Silva,b Eduarda Fernandes,a Marisa Freitasa a LAQV-REQUIMTE, Applied Chemistry Laboratory, Department of Chemical Sciences, Faculty of Pharmacy of the University of Porto, Porto, Portugal. bLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal Email: up201404164@ff.up.pt

Diabetes mellitus (DM), a chronic metabolic disorder of multiple etiology, is a major public health burden in the whole world. Besides hyperglycemia, this disease involves other aggravating factors, such as inflammation, that contribute to the progression and worsening of this condition. It is reported that neutrophils, as body’s first-line-defense cells, are greatly involved in the perpetuation of the inflammatory response under hyperglycemic conditions. This occurs not only due to their production of prodigious quantities of reactive species (RS), but also due to their specific type of cellular death (NETosis), through neutrophil extracellular traps (NETs) release. There is a growing scientific interest to find alternatives to the currently used anti-diabetic drugs, which are able to modulate RS and NETs production, playing this way an important role in the improvement of DM. Chalcones, plant-derived compounds that are part of our daily diet, present a 1,3-diaryl-2-propen1-one scaffold (Figure 1), and are known for their antioxidant and anti-inflammatory properties. Therefore, the question about the potential of these compounds to exert a positive effect in the DM status requires due atention.1,2 Our aim was to study the ability of a panel of 25 structurally related chalcones to modulate the RS production by human neutrophils, in physiological and in hyperglycemic conditions, simulating DM status. These chalcones vary from each other in the number and position of several substituents (hydroxyl, methoxyl, methyl or chlorine). The most active chalcones were also explored in their ability to modulate NETs production by human neutrophils. For this purpose, human neutrophils were isolated and stimulated with phorbol 12-myristate-13-acetate, to induce the production of RS and the occurrence of NETosis.3 Several chalcones exhibited an interesting modulatory effect against RS production, with IC50 values ≤5 μM. The majority of the tested chalcones presented similar effects in physiological and hyperglycemic conditions. Contrariwise, regarding NETs release, 2’,4’,6’,3,4pentahydroxychalcone, was the only one that presented an inhibitory effect. The obtained results clearly suggest that chalcones can be considered a promising therapeutic opportunity with potential benefits to be used as modulators of the inflammatory response triggered in DM.

Figure 1: General chemical structure and numbering system of chalcones. Acknowledgements: The work was supported by UID/QUI/50006/2019 with funding from FCT/MCTES through national funds and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI-010145-FEDER-029241). References: 1. S. Rocha, D. Ribeiro, E. Fernandes, M. Freitas, Curr. Med. Chem. 2018, 25. 2. S. Rocha, A. Sousa, D. Ribeiro, C. M. Correia, V. L. M. Silva, C. M. M. Santos, A. M. S. Silva, A. N. Araújo, E. Fernandes, M. Freitas, Food Funct. 2019, 10. 3. M. Freitas, G. Porto, J. L. F. C. Lima, E. Fernandes, Clin. Biochem. 2008, 41.

OC31

Rosamine fluorophores: improvements on the Friedel–Crafts acylation using microwave and ohmic heating Andreia Leite,a Carla Queirós,a Inês C. S. Cardoso,b Vera L. M. Silva,b Ana I. M. C. Lobo Ferreira,c Luís M. N. B. F. Santos,c Ana M. G. Silva,a,* Maria Rangeld a

REQUIMTE-LAQV, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, 4169-007 Porto. b REQUIMTE-LAQV, Departamento de Química, Universidade de Aveiro, 3010-193 Aveiro. c Centro de Investigação em Química (CIQUP), Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, 4169007 Porto. d REQUIMTE-LAQV, Instituto de Ciências Biomédicas de Abel Salazar, 4099-003 Porto.

Email: ana.silva@fc.up.pt

Rosamines are interesting and versatile fluorophores that belong to the family of xanthenes. These fluorophores offer different degrees of functionalization at both N atoms at 3- and 6positions, at the central 9-position aryl ring, and at the xanthene ring itself (Scheme 1). Due to their high molar absorptivity and intense fluorescence spectrum in the visible region, rosamines have been successfully used for different optical applications, as bioimaging probes or as fluorescent chemosensors.1 Compared to rhodamine synthesis, which involves two sequential Friedel–Crafts acylation reactions of an asymmetric anhydride with two equivalents of a m-aminophenol (forming a mixture of regioisomers), rosamines, which lack the carboxylic acid group in the o-position of the 9-phenyl ring, can be easily isolated as a single regioisomer, and are therefore less problematic to synthesize and purify. Herein we describe the synthesis of a series of 9-aryl-substituted rosamines,2 aiming to achieve fluorophores with photophysical properties suitable for sensing applications. The synthetic strategy involved the acid catalyzed condensation of the appropriate aldehyde with 3-(diethylamino)phenol, followed by oxidative cyclization. Results obtained using conventional heating, microwave irradiation and ohmic heating3 will be present, as well as the most relevant photophysical properties of fluorophores prepared.

Scheme 1: Strategy for the synthesis of rosamine derivatives Acknowledgements: We thank European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia), under the Partnership Agreement PT2020 through projects UID/QUI/50006/2019 and PTDC/QUI-QOR/29426/2017 (X-Sensors), FCT UID/QUI/00062/2019 (QOPNA) and UIDB/50006/2020 (LAQV-

REQUIMTE). C.I.Q.U.P. also thanks FCT, European Social Fund (ESF) for the project CIQUP, University of Porto (UID/QUI/0081/2019). AL, AIMCLF, VS and AMGS are financed by national funds through the FCT - I.P., in the framework of the execution of the program contract provided in paragraphs 4, 5 and 6 of art. 23 of Law no. 57/2016 of 29 August, as amended by Law no. 57/2017 of 19 July. References: 1. a) M. Beija, C. A. M. Afonso, J. M. G. Martinho, Chem. Soc. Rev. 2009, 38, 2410. b) R. Zhang, F. Yan, Y. Huang, D. Kong, Q. Ye, J. Xu, L. Chen, RSC Adv. 2016, 6, 50732. c) L. Wang, W. Du, Z. Hu, K. Uvdal, L. Li, W. Huang, Angew. Chem. Int. Ed. 2019, 58, 14026. 2. a) A. Leite, L. Cunha-Silva, D. Silva, A. I. M. C. Lobo Ferreira, L. M. N. B. F. Santos, I. C. S. Cardoso, V. L. M. Silva, M. Rangel, A. M. G. Silva, Chem. Eur. J. 2019, https://doi.org/10.1002/chem.201903313. b) I. C. S. Cardoso, A. L. Amorim, C. Queirós, S. C. Lopes, P. Gameiro, B. de Castro, M. Rangel, A. M. G. Silva, Eur. J. Org. Chem. 2012, 5810. 3. a) J. Pinto, V. L. M. Silva, A. M. G. Silva, A. M. S. Silva, J. C. S. Costa, L. M. N. B. F. Santos, R. Enes, J. A. S. Cavaleiro, A. A. M. O. S. Vicente, J. A. C. Teixeira, Green Chem. 2013, 15, 970. b) V. L. M. Silva, A. M. S. Silva, A. M. G. Silva, J. Pinto, R. Enes, J. A. S. Cavaleiro, A. A. M. O. S. Vicente, J. A. C. Teixeira, A. Morais, Reator Para Síntese Química Com Aquecimento óhmico, Método e Suas Aplicações, Portuguese patent No. 105908.

Poster Communications

Catalysis PC1

Monoamine oxidase: a versatile tool in amine resolution and functionalization Vasco F. Batista, Diana C. G. A. Pinto, Artur M. S. Silva LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. Email: vfb@ua.pt

Biocatalysis continues to assume an increasingly important role in synthetic and industrial chemistry, combining unmatched selectivity with environment-friendly processes. Monoamine oxidases (MAO) are at the forefront of this change, providing an exceptional path towards a wide range of different amines, including α-chiral amines. These enzymes were applied to metabolic engineering and multienzymatic pathways, for the synthesis of benzylisoquinoline alkaloids, and to amine resolution using MAO from Aspergillus niger. Enzyme engineering experiments significantly increased its substrate scope, allowing the oxidation of a broad range of α-aliphatic and aromatic amines. MAO-N was also applied to several bio-bio and bio-chemo cascades for amine functionalization, exploring the increased reactivity of the imine/iminium species (Figure 1).1,2 In this work we present an in-depth analysis of current research in the biocatalytic applications of MAOs, systematizing the activity and selectivity of different MAO variants towards α-chiral amines. Furthermore, we debate about the limitations and challenges that still hinder their widespread industrial application and evaluate paths for further development.3

Figure 1: The applications of MAO in biocatalysis. Acknowledgements: Thanks are due to the University of Aveiro and FCT/MCT for the financial support for the QOPNA research Unit (UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) through national funds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. Vasco F. Batista also thanks FCT for his PhD grant (PD/BD/135099/2017). References: 1. G. Grogan, Curr. Opin. Chem. Biol. 2018, 43, 15-22. 2. C. Curado-Carballada, F. Feixas, S. Osuna, Adv. Synth. Catal. 2019, 361, 2718-2726. 3. V. Batista, J. Galman, D. Pinto, A. Silva, N. Turner, ACS Catal. 2018, 8, 11889-11907.

Catalysis PC2

Catalytic sequential reactions in organic synthesis: novel strategies for multifunctionalization of olefins Mariette M. Pereira,a Fábio M. S. Rodrigues,a Lucas D. Dias,a,b Liliana Damas,a Andreia C. S. Gonzalez,a Rui M. B. Carrilhoa a

CQC, Department of Chemistry, University of Coimbra, Coimbra, Portugal; bSão Carlos Institute of Physics, University of São Paulo, Brazil Email: mmpereira@qui.uc.pt

Modern organic synthesis demands for high efficiency in terms of minimization of synthetic steps, reduction of residues and increment of chemical functionalization.1 Chemical processes able to generate new chemical bonds, leading to an increase of structural complexity using the shortest synthetic route is one of the greatest challenges of this decade for chemists worldwide. In this context, the development of sequential catalytic processes which allow the formation of multiple CC, C-H or C-O bonds through one-pot processes are of upmost relevance.2-4 In this communication, we present our recent achievements on the development of efficient and reusable immobilized catalysts to promote sequential processes for multifunctionalization of olefins, starting from catalytic olefin hydroformylation or epoxidation as central reactions (Scheme 1). Recently, we developed active and selective rhodium/phosphorus-based catalysts (CAT1) capable of promoting the transformation of substituted olefins into aldehydes. In addition, when the reactions were performed in the presence of a Ru-based Shvo‘s complex or iron(II)-scorpionate catalysts (CAT2, CAT3), the processes allowed the effective one-pot synthesis of alcohols and acetals.2,3 In addition, highly selective tetrapyrrolic macrocycle-based catalysts (CAT4) were applied in olefin epoxidation (using either O2 or H2O2 as green oxidants), followed by the one-pot sequential addition of CO2 as renewable raw material (CAT5), in order to obtain cyclic carbonates versus polycarbonates,4,5 or by ring-opening in the presence of amine nucleophiles (CAT6), leading to amino alcohols. These sequential processes have been applied to a variety of substrates, including vinyl-aromatics, natural-based terpenes and steroids, leading to the synthetic preparation of value-added products with multiple functionalities.

Scheme 1: Sequential catalytic processes for multi-functionalization of olefins. Acknowledgements: The authors thank Fundação para a Ciência e a Tecnologia (FCT) for funding the Coimbra Chemistry Centre through projects UID/QUI/00313/2019, CENTRO-010145-FEDER-00014 and POCI-01-0145-FEDER-016387. F.M.S.R. thanks FCT for PhD grant PD/BD/114340/2016 and L.D.D. thanks Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for post-doc grant 2019/13569-8. References: 1. P.T. Anastas, J.B. Zimmerman, Green Chem., 2019, Advance Article, DOI: 10.1039/C9GC01293A. 2. F. M. S. Rodrigues, P. K. Kucmierczyk, M. Pineiro, R. Jackstell, R. Franke, M. M. Pereira, M. Beller, ChemSusChem 2018, 11, 2310-2314. 3. F. M. S. Rodrigues, M. J. F. Calvete, C. J. P. Monteiro, S. A. C. Carabineiro, T. M. R. Maria, J. L. Figueiredo, M.M. Pereira, Catalysis Today 2019, in press, DOI: 10.1016/j.cattod.2019.05.045. 4. L. D. Dias, R. M. B. Carrilho, C. A. Henriques, M. J. F. Calvete, A. M. Masdeu-Bultó, C. Claver, L. M. Rossi, M. M. Pereira, ChemCatChem 2018, 10, 2792-2803. 5. R. M. B. Carrilho, L. D. Dias, R. Rivas, M. M. Pereira, C. Claver, A. M. Masdeu-Bultó, Catalysts 2017, 7, 210.

Catalysis PC3

Enantioselective alkynylation of aldehydes under mild and cheap conditions: ligand screening and optimization studies Nélia C. T. Tavares, Dina Murtinho, Maria Elisa S. Serra Chemistry Center and Department of Chemistry, University of Coimbra, Rua Larga 3004-535, Coimbra, Portugal.

Email: neliatadeu@hotmail.com

Enantioenriched propargylic alcohols are known to be versatile building blocks in organic synthesis. The unique reactivity of these compounds, that combine the alcohol and the alkyne moieties, makes them interesting and important intermediates in the synthesis of complex organic architectures, such as natural products and pharmaceuticals. One of the most effective tools for the obtention of such compounds is the addition of an acetylide to prochiral aldehydes or ketones, with the generation of a new stereogenic center. When in presence of efficient chiral ligands, the reaction proceeds in an enantioselective manner, affording optically active products.1 So far, the most efficient methods to perform this type of reaction are based on the use of zinc acetylides and, in spite of affording good results, the reaction conditions are far from ideal. The most efficient ligands are synthetically or commercially expensive, and their use is often accompanied by high catalyst loadings, harsh reaction conditions, and the use of additives. Additionally, the use of less reactive dimethylzinc instead of diethylzinc increases the cost of the process.2 Aiming to create a mild and cheaper chiral environment for the enantioselective alkynylation of aldehydes, we were prompted to investigate the selectivity of a spectra of ligands and conditions in the addition of phenylacetylene to benzaldehyde, mediated by diethylzinc (Scheme 1). Several camphoric acid derived imines and amines, thiazolidines and pyrrolidines were tested and complete conversions were obtained. Simple and cheap Lcysteine and D-penicillamine based thiazolidines were able to induce good enantioselectivity, up to 79:21 er, and, depending on the reaction conditions, suppress the competitive ethylation process.

Scheme 1: Enantioselective alkynylation of benzaldehyde promoted by chiral thiazolidines as ligands. Acknowledgements: We thank to Coimbra Chemistry Centre (CQC), supported by the Portuguese Agency for Scientific Research, Fundação para a Ciência e a Tecnologia (FCT) through Project Nº 007630 UID/QUI/ 00313/2013, cofounded by COMPETE2020-UE. Nelia C. T. Tavares also thank FCT for funding (PhD grant PD/BD/128496/2017). We also acknowledge the UC-NMR facility for obtaining the NMR data (www.nmrccc.uc.pt). References: 1. a) V. Bisai, V. K. Singh, Tetrahedron Letters 2016, 57, 4771. b) G. Lu, Y. Li, X. Li, A.S.C. Chan, Coordination Chemistry Reviews 2005, 249, 1736. 2. T. Bauer, Coordination Chemistry Reviews 2015, 299, 83.

Computational methods and drug design PC4

Targeting neuroinflammation: a combined virtual screening protocol towards the discovery of interleukin-1 receptor type I (IL1R1) modulators João P. Luís,a Carlos J. V. Simões,a,b Rui M. M. Britoa,b a

CQC, Chemistry Department, Faculty of Science and Technology, University of Coimbra, 3004-535 Coimbra, Portugal. bBSIM Therapeutics, Instituto Pedro Nunes, 3030-19 9 Coimbra, Portugal Email: jluis@student.ff.uc.pt

In recent years, neuroinflammation has been increasingly recognized as a major determinant of several neurodegenerative and central nervous system (CNS) disorders. Hence, the modulation of neuroinflammatory processes holds potential prospects for halting, or at least slowing down, the progression of such disorders.1 One of the most important group of cytokines implicated in neuroinflammation is the interleukin-1 (IL-1) family, a well-characterized cluster that plays a critical role in acute inflammatory responses.2 Importantly, several reports have demonstrated that blocking the IL-1 signalling pathway via interleukin-1 receptor type 1 (IL-1R1) leads to reduced neuroinflammation and may prevent related disorders.3 Notably, while there is substantial body of research on IL-1R1, there have been no small molecule modulators reported to date. Herein, we present the results of an integrated structure-based virtual screening protocol targeting the extracellular domain of IL-1R1, combining molecular dynamics (MD) simulation studies, 3D-pharmacophore modelling, and molecular docking – towards the discovery of small-molecule modulators of IL-1R1 and related molecular networks. Binding site prediction followed a grid-based pocket detection methodology prioritizing druggable cavities. This has been accompanied by the study of receptor dynamics via MD runs totalling 600 ns, with particular focus on the stability and conformational flexibility of the putative ligand-binding site. Several receptor-based pharmacophore hypotheses were then generated, which allowed retrieval of 13.814 virtual hit compounds from a CNStailored virtual screening deck. As a post-screening filter, said screening hits were docked into IL-1R1, with the best candidates ranked via quantitative analysis of protein-ligand interactions, docking scores and pharmacophore fitness levels. Thus far, 21 promising compounds have been selected on a basis of prior bioactivity data and chemical diversity, and acquired from their respective chemical vendors for in vitro evaluation. The ongoing experimental validation, together with the innovative in silico framework presented here, represents a pioneering attempt to discover IL-1R1 small molecule modulators, and will hopefully shed light on their use as potential neuroinflammation modulators. Acknowledgements: João P. Luís thank the MedChemTrain PhD programme (PD/00147/2013) in Medicinal Chemistry - Foundation for Science and Technology (FCT), Ministry of Science, Technology, and Higher Education (MCTES) – for the grant of PhD fellowship. References: 1. R. M. Ransohoff, Science. 2016, 353(6301), 777. 2. S. S. Shaftel, W. S. Griffin, M. K. O'Banion, J Neuroinflammation. 2008, 5, 7. 3. E. A. Newell, B. P. Todd, J. Mahoney, A. A. Pieper, P. J. Ferguson, A. G. Bassuk, eNeuro. 2018, 5(2), e0385-17.2018.

Computational methods and drug design PC5

Development of hit molecules for hexokinase 2 inhibition: an attempt to target glycolysis and apoptosis in cancer cells Sara N. Garcia,a,b Rita C. Guedes,b M. Matilde Marquesa a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049001 Lisboa, Portugal; biMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal Email: sara.garcia@tecnico.ulisboa.pt

Glucose is regarded as the main fuel of cancer cells and the glycolytic pathway has been demonstrated as a potential target to be explored for cancer treatment. Several enzymes involved in glycolysis are overexpressed in different types of cancer cells, namely hexokinase 2 (HK2)1. This enzyme is not only involved in the first and most determinant step of glycolysis and subsequently in the different branched pathways2,3, but also in the immortalization of cancer cells. When catalytically active, HK2 is able to bind to the voltage-dependent anion channel (VDAC) in the mitochondrial outer membrane, preventing the normal pro-apoptotic signalling. HK2-VDAC disruption would promote the binding of pro-apoptotic proteins to VDAC, stimulating the enhancement of apoptosis in cancer cells4. In this way, the inhibition of the HK2 catalytic centre is proposed as a strategy to reduce the main source of energy to cancer cells, thus significantly decreasing cancer cell proliferation and avoiding HK2 binding to VDAC and thereby enhancing the apoptosis process As an effort to find hit compounds able to interfere with the HK2 catalytic activity, a structure-based drug design strategy was implemented, leading to the virtual screening of several general databases such as DrugBank (~2000 molecules), NCI (~265 000 molecules), Chemoteca (~800 molecules) and some specific natural product derivatives databases such as Ambinter (~10 000 000 molecules) and InterBioScreen Natural Products (~84 000 molecules). The structure-based virtual screening (SBVS) was carried out using molecular docking calculations through Gold 5.20 software. Molecules were prepared using Molecular Operating Environment (MOE2016 0802) and then docked into the HK2 catalytic site. Biochemical validation of the above-mentioned protocol was conducted using the ADP-GloTM kinase assay, a luminescence-based approach. Our in silico studies have identified 2981 molecules with the potential to act as new HK2 inhibitors. Preliminary results of biochemical evaluation with 64 selected molecules are presented. Twenty-two molecules were found to inhibit the HK2 activity more prominently or in the same range of the known inhibitor 3-bromopyruvate (3BP). The experimental data support the predictions of the SBVS procedure. All the 64 molecules tested in the kinase assay affect HK2 activity to some extent. The results demonstrate that the in silico procedure used herein can recognize bioactive molecules, ready for structural optimization and/or further testing. Acknowledgements: We thank Fundação para a Ciência e a Tecnologia for financial support (PD/BD/135284/2017, UID/DTP/04138/2019, UID/QUI/00100/2019, SAICTPAC/0019/2015, and PTDC/QUIQAN/32242/2017). References: 1. Hay, N. Nat. Rev. Cancer 2016, 16 (10), 635–649. 2. Martinez-Outschoorn, U. E.; Peiris-Pagès, M.; Pestell, R. G.; Sotgia, F.; Lisanti, M. P. Nat. Rev. Clin. Oncol. 2017, 14 (1), 11–31. 3. Hamanaka, R. B.; Chandel, N. S. J. Exp. Med. 2012, 209 (2), 211-215. 4. Krasnov, G. S.; Dmitriev, A. A.; Lakunina, V. A.; Kirpiy, A. A.; Kudryavtseva, A. V. Expert Opin. Ther. Targets 2013, 17, 1221–1233.

Computational methods and drug design PC6

Application of computational methods for discovery of novel BACE1 inhibitors: ligand- and structure-based protocols with in vitro evaluation Judite R. M. Coimbra,a,b Salete J. Baptista,b,c Maria M. C. Silva,a,b Teresa C. P. Dinis,b,d Paula I. Moreira,b,e Armanda E. Santos,b,d Jorge A. R. Salvadora,b aLaboratory

of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. bCNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. cChem4Pharma, Edifício IPN Incubadora, 3030-199 Coimbra, Portugal. dLaboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. eLaboratory of Physiology, Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal.

Email: Coimbra.jrm@gmail.com

The treatment options for a patient diagnosed with Alzheimer’s disease (AD) are seriously limited.1 Currently, the focus of disease-modifying approaches in AD research has been to prevent the neurodegenerative process. The accumulation of Amyloid-β (Aβ) neurotoxic oligomers has been pointed out as the critical molecular event in the pathogenesis of AD.2 The production of Aβ peptide could be reduced when the amyloidogenic secretase liable for the β-site processing of Amyloid precursor protein (APP) is inhibited (Figure 1).3 Henceforth, the BACE1 protease has been considered as the major therapeutic target in AD over the last years.4,5 This project was conducted by using combined molecular modeling methodologies, such as pharmacophore-based virtual screening and molecular docking with posterior biological evaluation of the most promising compounds. The generation of structure-based and ligand-based pharmacophore models were designed to identify promising anti-BACE1 agents from a large druglike compound database. Subsequently, the retrieved hits were further in silico filtered to predict their ability to cross the blood-brain barrier (BBB). Hence, molecular docking studies enabled the selection of the best candidates for in vitro screening bioassay. Lastly, some compounds were found as novel hits with BACE1 inhibitory activity at the micromolar level.

Figure 1: Scheme of the Aβ generation and the subsequent oligomerization and aggregation into plaques. Generation of Aβ by consecutive proteolytic process of APP by β- and γ-secretase. Potential therapeutic interventions for AD may involve the inhibition of BACE1.

Acknowledgements: This research was financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the projects CENTRO-01-0247-FEDER-003269 (Drugs2CAD) and CENTRO01-0145-FEDER-000012 (HealthyAging2020) and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, under project UID/NEU/04539/2019. JRMC also thanks FCT for funding the research grant SFRH/BD/138460/2018 and JARS acknowledges the financial support from the University of Coimbra. References: 1. Cummings J., et al. Alzheimer's disease drug development pipeline: 2018. Alzheimers Dement. (N Y) 2018, 4, 195-214. 2. Sharma P., et al. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog. Neurobiol. 2018, 174, 53-89. 3. Panza F., et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2019, 15, 7378. 4. Yan, R. Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs. Transl. Neurodegener. 2016, 5, 1-11. 5. Coimbra JRM. et al. Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment. Front. Chem. 2018, 6, 178.

Green chemistry PC7

Protocol refinement in tumour spheroid formation and machinelearning classification José Miguel P. Ferreira de Oliveira,a Samuel Alves,b Diogo Marcelo Nogueira,c Alípio M. Jorge,c,d Conceição Santos,b,e Eduarda Fernandesa a

LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. b Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal. cINESC TEC, Faculty of Engineering, University of Porto, Porto, Portugal. dDepartment of Computer Science, Faculty of Sciences, University of Porto, Porto, Portugal. eLAQV, REQUIMTE, Faculty of Sciences, University of Porto, Porto, Portugal. Email: jmoliveira@ff.up.pt

In vitro 3D models such as tumour spheroids are being increasingly applied in cancer research. Spheroid culture is amenable to high-throughput screening, particularly in the hanging-drop or ultra-low attachment formats. Spheroid size uniformity, shape and compactness are critical for achieving reproducible results since these features affect cell function and behavior, as well as drug penetration and transport.1 In this work, spheroid culture and subsequent machine-learning classification were investigated in the osteosarcoma MG-63 cell line. Regarding spheroid culture development, optimization was based on previously reported methods, with emphasis on different culture formats, encapsulation and aggregation methods, fetal bovine serum concentrations or conditions leading to inhibition of spheroid deposition.2,3 Subsequently, various parameters were analysed including cell culture conditions and spheroids characteristics, as spheroid size, estimated volume, circularity and compactness (Figure 1). Despite the formation of tumor spheroids of adequate sizes (200-400 µm), a range of variability was observed considering the intrinsic variability of the cellular growth and aggregation processes. Our next question was whether the developed high-throughput protocol produced spheroids that when grown under different conditions were amenable to machine-learning classification. After 3day growth, spheroids were additionally incubated in culture medium in the presence or absence of doxorubicin. To achieve a classification of treated vs. non-treated spheroids, a machine-learning approached was used. Spheroid images were divided in 2 groups, a training group and a test group. Subsequently, an MLP (multilayer perceptron) model was used with defined batch size (20), number of classes (2) and epoch number (70). In order to refine weight values, a backpropagation algorithm was employed. The developed program allowed a separation between treated and nontreated groups and can be considered a new tool for in vitro osteosarcoma research.

Figure 1: High-throughput 3D spheroid culture and analysis. Acknowledgements: This work was supported by European Regional Development Funds and National Funds (Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 POCI-010145-FEDER-007265-UID/QUI/50006/2019, and "Programa Operacional Competitividade e Internacionalização" (COMPETE) (POCI-01-0145-FEDER-029243). FCT/MCT supported J.M.P. Ferreira de Oliveira (grant number SFRH/BPD/74868/2010) as defined by Decree-Law No. 57/2016, of 29 August, amended by Law No. 57/2017, of 19 July. References: 1. M. Zanoni, F. Piccinini, C. Arienti, A. Zamagni, S. Santi, R. Polico, A. Bevilacqua, A. Tesei. Sci Rep. 2016,6,19103. 2. J. Friedrich, C. Seidel, R. Ebner, L.A. Kunz-Schughart, 2009. Nat. Protoc. 2009,4,309. 3. F. Ruedinger, A. Lavrentieva, C. Blume, I. Pepelanova, T. Scheper. Appl Microbiol Biotechnol. 2015,99,623.

Green chemistry PC8

A new method for aminal formation under mild conditions Juliana G. Pereira, Rafael F. A. Gomes, Jaime A. S. Coelho, Carlos A. M. Afonso iMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal Email: julianagpereira92@gmail.com

Aminals are the condensation product of aldehydes and secondary amines, structurally similar to acetals. These compounds have been used as intermediates, chiral auxiliaries and protection groups in reactions and also used in biology due to its biological activity. 1 The most common methodology for the formation of aminals involves the condensation of aldehydes with amines in ethanol or toluene under high temperature using dehydrating agents to remove the water in the reaction, shifting the equilibrium to the product.2 However, performing the reaction in aqueous media instead of organic solvents is a process environmentally competitive for the preparation of aminals. This work reports on the formation of aminals, from aromatic aldehydes and furfural derivatives with different secondary amines, in water under mild conditions.

NHR2 R

RHC(NR2)2 water

Scheme 1. Preparation of aminals with different aldehydes and secondary amines in water.

Acknowledgements: The authors thank the Fundação para a Ciência e Tecnologia (PD/BD/128316/2017, PTDC/QUI-QOR/32008/2017 and UID/DTP/04138/2013), COMPETE Programme (SAICTPAC/0019/2015) for financial support. References: 1

A. Alexakis, N. Lensen, P. Mangeney. Tetrahedron Letters, 1991, 32, 1171.

M. A. Ramirez, G. Ortiz, G. Levin, W. McCormack, M. M. Blanco, I. A. Perillo, A. Salerno, Tetrahedron

Letters, 2014, 55, 4774.

Green chemistry PC9

Optimization of kinetic parameters to assess glycogen phosphorylase activity using a microanalysis method Sónia Rocha,a Luísa Corvo,b Eduarda Fernandes,a Marisa Freitasa a LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. b Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal. Email: up201607090@ff.up.pt

Glycogen phosphorylase, the main enzyme involved in glycogen metabolism, is responsible for the release of glucose 1-phosphate from glycogen, with the cleavage of glycosidic bonds of the terminal glucose units of glycogen chains. The inhibition of this enzyme is an ongoing target with potential therapeutic applications in the treatment of type 2 diabetes.1 Based in the reversible reaction catalized by glycogen phosphorylase, different methods have been developed to evaluate the inhibitory activity of potential antidiabetic compounds. The most cited method is based on the colorimetric detection of the inorganic phosphate deriving from glucose 1-phosphate during glycogen synthesis.2 However, in the literature, the presence of several experimental variables related to the enzymatic kinetics gives rise to confusing results. Thus, the aim of the present study was to optimize the experimental conditions of this microanalysis assay to measure glycogen phosphorylase activity, using rabbit muscle glycogen phosphorylase a, which closely mimetics the human liver glycogen phosphorylase a. Various enzyme, glucose 1-phosphate and glycogen concentrations, as well as temperature and incubation times were evaluated. The results obtained allowed the choice of the optimal concentration of enzyme (0.375 U/mL), glucose 1-phosphate (0.25 mM), glycogen (0.25 mg/mL), and temperature (37ºC). Caffeine and CP-91149 (5chloro-N-[(1S,2R)-3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole2-carboxamide) were used as positive controls to validate the method. This optimized microanalysis assay will enable to standardize the in vitro inhibition of glycogen phosphorylase, using a high-throughput screening technique.

Acknowledgements: This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through grant UID/QUI/50006/2019, and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI-01-0145-FEDER-029241). Sónia Rocha acknowledges FCT the financial support for the PhD grant (PD/BD/145169/2019), in the ambit of “QREN – POPH - Tipologia 4.1 - Formação Avançada”, co-sponsored by Fundo Social Europeu (FSE) and by national funds of Ministério da Ciência, Tecnologia e Ensino Superior (MCTES).

References: 1. M. Donnier-Maréchal, S. Vidal, Expert. Opin. Ther. Pat. 2016, 26. 2. K. Szabó, L. Kandra, G. Gyémánt, Carbohydr. Res. 2019, 477.

Green chemistry PC10

One-pot mechanosynthesis and catalytic performance of tripodal metallic complexes Rima Tedjini,a,d,c Raquel Viveiros,c Teresa Casimiro,c Oualid Talhi,d Vasco D.B. Bonifáciob a

Laboratory of Applied Organic Chemistry, Faculty of Chemistry, University of Science and Technology Houari Boumediene, BP 32, Alia Bab-Ezzouar, 16111 Algiers, Algeria. bCQFM-IN and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049001 Lisboa, Portugal. cLAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, 2829-516 Caparica, Portugal. dResearch Center Scientific and Technical in Analyzes Physico-Chimiques CRAPC, BP384, Bou-Ismail, 42004 Tipaza, Algeria. Email: vasco.bonifacio@tecnico.ulisboa.pt

Catalysts green synthesis is the ultimate cumber stone of green catalysis. The emergence of green chemistry, fully engraved in the twelve principles,1 has been shaping reactions and protocols developed in the last decade, and certainly future chemistry and engineering processes and processing. For chemists, the options to embrace greener protocols are already available and may include, besides alternative solvents (e.g. ionic liquids, supercritical carbon dioxide), technologies such as microwave irradiation, ultrasound-assisted reactions, and mechanochemistry, all considered as technical innovations to achieve eco-friendly processes development.2-4 Specifically, mechanosynthesis, an emergent solventless approach, is a powerful tool regarding the synthesis of metallopharmaceuticals and catalysts.5,6 In this work we describe for the first time the synthesis and metal complexation of tripodal ligands by a simple, short and high yielding one-pot mechanochemical procedure using a planetary ball-mill. The performance of this novel catalysts was further investigated in H2O2-assisted oxidations (Scheme 1).

Scheme 1: Mechanosynthesis of green catalysts based on tripodal metallic complexes.

Acknowledgements: We thank Fundação para a Ciência e a Tecnologia (FC&T, Portugal) for funding through projects PTDC/MEC-ONC/29327/2017 and PTDC/EQU-EQU/32473/2017. Associate Laboratory for Green Chemistry LAQV-REQUIMTE is financed by national funds from FCT/MCTES (UID/QUI/50006/2019) and cofinanced by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER−007265). References: 1. R. B. N. Baig, R. S. Varma, Chem. Soc. Rev. 2012, 41, 1559. 2. M.B. Gawande, V.D.B. Bonifácio, R. Luque, P.S. Branco, R.S. Varma, Chem. Soc. Rev. 2013, 42, 5522. 3. J. Andersen, J. Mack, Green Chem, 2018, 20, 1435. 4. M. B. Gawande, V. D. B. Bonifácio, R. Luque, P. S. Branco, R. S. Varma, ChemSusChem 2014, 7, 24. 5. D. Tan, L. Loots, T. Friščić, Chem. Commun. 2016, 52, 7760. 6. C. Xu, S. De, A. M. Balu, M. Ojeda, R. Luque, Chem. Commun. 2015, 51, 6698.

Green chemistry PC11

Modern methods for the synthesis of metalloporphyrins Carla Gomes, Marta Pineiro CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal. Email: carla_sofia.gomes@live.com.pt

The “pigments of life”, are metal complexes of tetrapyrrolic macrocycles that play important roles in vital biological processes. Metalloporphyrins have been perfected by nature to give functional dyes for diverse applications, particularly, chlorophyll in photosynthesis, hemoglobin in the transport of oxygen and cytochrome in the activation of oxygen. Inspired by their roles in nature, synthetic metalloporphyrins have been developed to be used in catalysis, medicine, imaging, materials, detection of ions and molecules, etc.1-10 The metalloporphyrins needed for these applications are prepared by replacing the two H atoms at the central NH of the porphyrin core by a metal ion. One of the major difficulties of this reaction has been to find a reaction medium that allows the solubilization of both the metal salt and the organic compound. Classical approaches solved the problem by using high boiling solvents (DMF) or mixtures of chlorinated solvents with alcohols (CHCl3/MeOH) and large excess of the metal salt (M(OAc)2; MX2; etc).11 Neither the use of those organic solvents nor the large excess of metal salts are in line with current chemistry practices or present environmental concerns. Therefore, we focused our efforts on the sustainable synthesis of metalloporphyrins. Herein we will discuss two methodologies developed, depending on the hydrophilicity of the porphyrin core. Hydrophobic metalloporphyrins of the first row transition metals and group 10 of the Periodic Table were prepared under mechanical activation, under solventfree conditions using only 5 equivalents of the corresponding metal salt. Those complexes were obtained in high yield after purification by liquid-liquid extraction. Hydrophylic metalloporphyrins were derivatized under ultrasound irradiation using water as solvent and equimolar quantities of the metal salt. The purification of these complexes requires molecular exclusion chromatography or dialysis purification processes. Both methodologies are in good agreement with Green Chemistry principles as demonstrated by the good values obtained in several Green Chemistry metrics. NH

N M

Figure 1. Synthesis of metalloporphyrins under microwave, ultrasound and mechanochemical conditions. Acknowledgements: We thank the FCT for financial support (Carla Gomes - FCT- PD/BD/135531/2018 – CATSUS FCT-PhD Program; Strategic Projects: UID/QUI/00313/2019-CQC supported by the Portuguese Foundation for Science and Technology (FCT). References: 1.Costas, M. Coord. Chem. Rev. 2011, 255, 2912-2931. 2. Shao, S.; Rajendiran, V.; Lovell, J.F. Coord. Chem. Rev. 2019, 379, 99-120.3. Simonneaux, G.; Maux, P.L.; Ferrand, Y.; Rault-Berthelot, J. Coord. Chem. Rev. 2006, 250, 22122221.4.Doctorovich, F.; Bikiel, D.; Pellegrino, J.; Suárez, S.A.; Larsen, A.; Martí, M.A. Coord. Chem. Rev. 2011, 255, 27642784. 5. Dąbrowski, J.M.; Pucelik, B.; Regiel-Futyra, A.; Brindell, M.; Mazuryk, O.; Kyzioł, A.; Stochel, G.; Macyk, W.; Arnaut, L.G. Coord. Chem. Rev. 2016, 325, 67-101. 6. Pratviel, G. Coord. Chem. Rev. 2016, 308, 460-477. 7. Jurow, M.; Schuckman, A.E.; Batteas, J.D.; Drain, C.M. Coord. Chem. Rev. 2010, 254, 2297-2310. 8. Valderrey, V.; Aragay, G.; Ballester, P. Coord. Chem. Rev. 2014, 258-259, 137-156. 9. Calvete, M.J.F.; Pinto, S.M.A.; Pereira, M.M.; Geraldes, C.F.G.C. Coord. Chem. Rev. 2017, 333, 82-107.10. Kielmann, M.; Prior, C.; Senge, M. O. New J. Chem, 2018, 42, 75297550. 11.Smith, K.M. Porphyrins and metalloporphyrins. Elsevier: Amsterdam-NewYork-Oxford, 1975.

Materials chemistry PC12

Development of novel antimicrobial celluloses Declan C. Mullen,a Atiya Sarmin,b John Connelly,b Louise Young,a John A. Parkinson,c Vânia M. Moreiraa,d,e a

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, United Kingdom, 161 Cathedral Street, G4 0RE Glasgow. bCentre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London. cDepartment of Pure & Applied Chemistry, University of Strathclyde, United Kingdom, 295 Cathedral Street, Glasgow G1 1XL. dLaboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal eCenter for Neuroscience and Cell Biology, University of Coimbra,004-504 Coimbra, Portugal. E-mail: declan.mullen@strath.ac.uk

Microorganisms have the innate ability to evolve and adapt to survive exposure to external stimuli such as antibiotics, thus resulting in the emergence of the phenomenon known as antimicrobial resistance (AMR).1 AMR presents a major threat to the continued health of the global populace as widespread resistance becomes more common. For instance, strains of S. aureus, a common post-surgical infection, have emerged which are resistant to the antibiotic methicillin severely complicating the healing of infected chronic/surgical wounds. Previous work in our group showed that amino acid functionalised dehydroabietic acid derivatives are capable of killing planktonic bacteria and limit their ability to form biofilms.2 The group has also shown that the functionalisation of nanocellulose with abietanes resulted in innovative and cost-efficient eco-friendly surfaces with antimicrobial properties and good biocompatibility.3 As the primary structural component of the plant cell wall, cellulose is the most common organic compound on the planet. It can be harvested and processed from many different renewable plant sources such as wood and cotton.4 This combination of renewability, low cost, strong structural integrity and its innate noncytotoxic properties make it an ideal basis for development of new antimicrobial biomaterials.3,4 The goal of our current work is to build from this knowledge and chemically modify medically relevant biopolymeric substances, such as nano- and carboxymethyl-cellulose, with our in-house library of antimicrobial abietanes to produce materials with innate antibacterial properties and explore their potential applications in wound-healing as both films and hydrogels. Acknowledgements: We thank Tenovus Scotland (project S18-23) and The Engineering and Physical Sciences Research Council (EPSRC) for financial support. References 1. J. O’Neill, ‘Anti-Microbial Resistance: Tackling a Crisis for the Health and Wealth of Nations’, 2014, https://amrreview.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20h ealth%20and%20wealth%20of%20nations_1.pdf (Accessed: May 2019) 2. a) S. Manner, M. Vahermo, M. E. Skogman, S. Krogerus, P. M. Vuorela, J. Yli-Kauhaluoma, A. Fallarero, V. M. Moreira, Eur. J. Med. Chem. 2015, 102, 68-79. b) A. Helfenstein, M. Vahermo, D. A. Nawrot, F. Demirci, G. Işcan, S. Krogerus, J. Yli-Kauhaluoma, V. M. Moreira, P. Tammela, Bioorg. Med. Chem, 2017, 25, 132. c) A. Fallarero, M. Skogman, J. Kujala, M. Rajaratnam, V. M. Moreira, J. Yli-Kauhaluoma, P. Vuorela, Int. J. Mol. Sci. 2013, 14, 12054. 3. G. Hassan, N. Forsman, X. Wan, L. Keurulainen, L. M. Bimbo, L.-S. Johansson, N. Sipari, J. YliKauhaluoma, S. Stehl, C. Werner, P. E. J. Saris, M. Österberg, V. M. Moreira, ACS Sust. Chem. Eng., 2019, 7, 5002. 4. a) C. Schultz, J. Van Rie, S. Eyley, A. Gençer, H. van Gorp, S. Rosenfeldt, K. Kang, W. Thielemans, ACS Sustainable Chem. Eng., 2018, 67, 8317. b) N. Lin, A. Dufresne, Eur. Pol. J., 2014, 59, 302. c) A. H. Tayeb, E. Amini, S. Ghasemi, M. Tajvidi, Molecules, 2018, 23(10), 2684.

Materials chemistry PC13

Ionic liquids as a strategy to improve drug delivery systems Ana Júlio,a,b Rita Caparica,a,b Ana Sofia Fernandes,a Catarina Rosado,a Nuno Saraiva,a Maria E. M. Araújo,c André R. Baby,d João G. Costa,a Pedro Fonte,a,e f Joana Portugal Mota,a Tânia Santos de Almeidaa,c a

CBIOS-Research Center for Biosciences and Health Technologies, Lusófona University, Lisbon, Portugal. b Department of Biomedical Sciences, University of Alcalá, Alcalá de Henares, Spain. cCQB, CQE and Department of Chemistry and Biochemistry, Faculty of Sciencies, University of Lisbon, Lisbon, Portugal. d School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bloco 15, 05508900, São Paulo, Brazil. eLAQV, REQUIMTE, Department of Chemical Sciences – Applied Chemistry Lab, Faculty of Pharmacy, University of Porto, Porto, Portugal. fiBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, University of Lisbon, Lisbon, Portugal. Email: tania.almeida@ulusofona.pt

The development of drug delivery systems with high drug efficacy and safety is one of the major concerns of the Pharmaceutical and Cosmetic Industries. Nonetheless, there are several challenges to overcome when trying to formulate new delivery systems, such as poor drug solubility, loading or release and low stability of these systems. Hence, a great amount of financial resources is spent trying to overcome these weaknesses. Finding new functional excipients that improve the performance of these systems may help to surpass some of these drawbacks. With this in mind, ionic liquids (ILs) may be potential candidates as functional excipients, since their chemical structure can be tailored to achieve the most suitable properties, accordingly to the desired applicability, and they may be introduced in various solutions, thus improving the chances of successfully incorporating these salts into different types of delivery systems1,2. Thus, in this study, several ILs were synthesized and their applicability as functional excipients, at non-toxic concentrations, is evaluated in different delivery systems. Six ILs were prepared, three choline-aminoacid ILs, (2-hydroxyethyl)–trimethylammonium-L-phenylalaninate [Cho][Phe], (2hydroxyethyl)–trimethylammonium-L-glutamate [Cho][Glu] and (2-hydroxyethyl) trimethylammonium glycinate [Cho][Gly], and three imidazole-based ILs, 1-ethyl-3methylimidazolium bromide [C2mim][Br], 1-butyl-3-methylimidazolium bromide [C4mim][Br] and 1hexyl-3-methylimidazolium bromide [C6mim][Br] and their cytotoxicity in human keratinocytes (HaCat) was evaluated. Then, considering these results, several delivery systems, such as oil-inwater (O/W) emulsions, gels, lipidic implants and hybrid IL-nanocarriers, were prepared in the presence and absence of the ILs. Each IL was incorporated at the upper concentration of these salts that allows the maintenance of cell viability, accordingly with the cytotoxicity results. The results showed that the ILs enhance the solubility of all the studied drugs and when incorporated in the delivery systems they allowed a significantly higher drug loading, with the choline based ILs displaying better results1,2,3. All topical formulations, O/W emulsions and gels, proved to be stable in the presence of the ILs. Concerning the lipidic implants, the incorporation of the ILs on these systems showed that they seem to modulate the release profile of the drug. Stable and robust IL-polymer nanoparticle hybrid systems were also developed, showing that the presence of ILs allows a higher drug loading. Our results indicated that the incorporation of ILs, at concentrations where cell viability is maintained, allowed the development of more efficient drug delivery systems, thus showing that these salts may be valuable as functional excipients. Acknowledgements: This work was supported by Fundação para a Ciência e Tecnologia, I.P., through funding UID/DTP/04567/2019. A.J. and R.C. would like to thank ALIES for the grant PADDIC 2018-2019. References: 1. A. Júlio, R. Caparica, S. A. Costa Lima, A. S. Fernandes, C. Rosado, D. M. F. Prazeres, S. Reis, T. Santos de Almeida, P. Fonte, Nanomaterials 2019, 9, 1148. 2. R. Caparica, A. Júlio, A. R. Baby, M. E. M. Araújo, A. S. Fernandes, J. G. Costa, T. Santos de Almeida, Pharmaceutics 2018, 10, 288. 3. T. Santos de Almeida, A. Júlio, N. Saraiva, A. S. Fernandes, M. E. M. Araújo, A. R. Baby, C. Rosado, J. Portugal Mota, Drug Development and Industrial Pharmacy, 2017, 43, 1858.

Materials chemistry PC14

Synthesis of functional naphthalene diimides for photoactive materials M. Bernardo, A.D.G. Firmino, C. Baleizão CQE-Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal Email: miguelmbernardo@tecnico.ulisboa.pt

Naphthalene diimides (NDIs) exhibit interesting properties such as high electron affinity, good charge carrying mobility, excellent thermal and oxidative stability, that are key points for electronic applications. Additionally, the synthetic pathways for derivatization, to include functional groups or tune the solubility, are straightforward, making these compounds promising candidates to develop a wide range of photoactive materials.1 In the context of energy-related applications, metal-organic frameworks (MOFs) are attracting a wide interest, due to their semiconductor behavior and synthetic flexibility. Therefore, the preparation of these hybrid materials combining the unusual properties of NDIs and MOFs, will result in enhanced materials for cutting-edge energy applications.2 In this work, we present the preparation of carboxylic and phosphonic acid functionalized NDIs, starting from the corresponding anhydride (Scheme 1), highlighting the faced challenges and the use of sustainable synthetic methods.

Scheme 1 – NDIs synthesis through convergent approach.

Acknowledgements: This work was supported by Fundos Europeus Estruturais e de Investimento (FEEI), Programa Operacional Regional de Lisboa-FEDER (02/SAICT/2017), and national funds from Fundação para a Ciência e a Tecnologia (FCT-Portugal) and COMPETE (FEDER) within projects PTDC/CTMCTM/32444/2017 (02/SAICT/2017/032444), PTDC/CTM-POL/3698/2014, and UID/QUI/00100/2019 (CQE). References: 1.M. A. Kobaisi, S. V. Bhosale, K. Latham, A. M. Raynor, S. V. Bhosale, Chem. Rev. 2016, 116, 11685-11796. 2. V. Stavila, A. A. Talin, M. D. Allendorf, Chem. Soc. Rev. 2014, 43, 5994-6010.

Materials chemistry PC15

Synthesis and photophysical characterization of triphenylpyridine fluorophores Luís Fontes,a Raquel Nunes da Silva,a,b João Rocha,c Artur M. S. Silva,a Samuel Guieua,c a

LAQV-Requimte, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal; b Department of Medical Sciences and Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal; c CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. Email: lfontes@ua.pt; sguieu@ua.pt

In this study, triphenylpyridine derivatives were synthesized and fully characterized, including their photophysical properties. The triphenylpyridine core presented fluorescence in solution with high quantum yields when substituted with a methoxy group, but not with a phenol hydrogen bonded to the pyridine nitrogen. Nevertheless, all fluorophores are emissive in the solid state, presenting aggregation-induced emission1,2 This feature was rationalized by the study of their crystal structures, presenting only very weak intermolecular interactions and an efficient stiffening of the structure. Triphenylpyridine is therefore a promising scaffold for the preparation of luminescent organic materials.

Scheme 1 Synthesis of triphenylpyridine fluorophores and dropcasted solids view under a UV lamp. Acknowledgements: Thanks are due to University of Aveiro, FCT/MEC for the financial support to the QOPNA research Unit (FCT UID/QUI/00062/2019), the LAQV-REQUIMTE (UIDB/50006/2020) and also to the Portuguese NMR Network. This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/ 50011/2019, financed by national funds through the FCT/MCTES. S. Guieu acknowledges the fundings from national funds (OE), through FCT – Fundação para a Ciência e a Tecnologia , I.P., in the scope of the framework contract foreseen in the numbers 4, 5 and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19, and from the Integrated Programme of SR&TD “pAGE – Protein aggregation Across the Lifespan” (reference CENTRO-01-0145-FEDER000003), including R. Nunes da Silva Post-Doctoral grant (BPD/UI98/6327/2018). References: 1. Guieu, S., Cardona, F., Rocha, J. & Silva, A. M. S. Tunable Color of Aggregation-Induced Emission Enhancement in a Family of Hydrogen-Bonded Azines and Schiff Bases. Chem. - A Eur. J. 24, 17262–17267 (2018) 2. Hong, Y., Lam, J. W. Y. & Tang, B. Z. Aggregation-induced emission. Chem. Soc. Rev. 40, 5361 (2011)

Materials chemistry PC16

New co-crystals of ketoconazole Daniela Silva,a M. Fátima M. Piedade,a,b Hermínio P. Diogoa a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa,1049-001 Lisboa, Portugal. bCentro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1649-016 Lisboa, Portugal.

Email: daniela.filipa.2710@hotmail.com

Ketoconazole is an oral antifungal agent with poor water-solubility and an erratic bioavailability which translates into an insufficient therapeutic window. Synthesis of cocrystals or salts is a promising pathway to mitigate this disadvantage, and also appropriate to produce newly species where the molecule of interest is kept intact preserving its pharmacological properties.1 There are different methods of synthesis of these multicomponent forms such as solution methods, mechanochemical methods or by using microwave radiation. However, different methods of preparation can lead to different compounds even if starting materials from identical batches are used. The assessment of the stability of a specific binary cocrystal or salt relative to its precursors, therefore, becomes of considerable importance. In this work are presented three new cocrystals of ketoconazole with dicarboxilic acids as co-formers (Figure 1). Firstly, commercial samples purity was evaluated by High Performance Liquid Chromatography techniques coupled to the Mass Spectrometry (HPLC-MS). Then, cocrystallization was made through the different techniques referred above, like mechanochemistry, solution and microwave. The compounds obtained were characterized by X-ray diffraction (single crystal and powder diffraction), differential scanning calorimetry (DSC), thermogravimetry (TGA) and microscopy data (HSM). Crystallization of the new multicomponent forms was done by solvent evaporation.

Figure 1: Scheme of the reaction of Ketoconazol with Azelaic Acid obtained by mechanochemistry.

Acknowledgements: This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal through Projects PTDC/QUI-OUT/28401/2017 (LISBOA-01-0145-FEDER-028401), UID/MULTI/00612/2013, and UID/QUI/00100/2013. A grant awarded by FCT to D. Silva (BL81/2019_IST-ID) was acknowledged. References: 1. F. A. Martin, M. M. Pop, G. Borodi, X. Filip, I. Kacso, Cryst. Growth Des. 2013, 13, 4295-4304.

Materials chemistry PC17

Photoactive systems based on corrole macrocycles and nanoparticles Joana F.B. Barata,a Tito Trindade,b M. Graça P. M. S. Neves,c Gabriela Matos,b Paula Lacerda,a Ana L. Daniel-da-Silva,b Rute Pereira,b José Cavaleiroc a

CESAM and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; b CICECO and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; c LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; Email: jbarata@ua.pt

Corroles, aromatic tetrapyrrolic macrocycles with a direct C-C linkage between two adjacent pyrrole rings , have distinctive structural and unique chemical/photophysical properties such as strong light absorption, high emission, and an efficient ability to generate cytotoxic oxygen species.1 These are fundamental properties that allow the development of new corrole macrocycles to be used in several fields, such as sensors, dye sensitized solar cells and in medicine. In fact, the use of corroles in medicine, namely as photosensitizers in photodynamic therapy have been recently evaluated.2 In this context, we have been interested in the development of new hybrid materials comprising corrole molecules with inorganic nanoparticles.3,4 In this communication, it will be discussed how simple transformations conducted in this type of macrocycles can afford compounds to be chemical grafted onto the surfaces of inorganic nanoparticles such as silica nanoparticles and magnetic nanoparticles. The influence of the chemical nature of the functionalized corroles on the morphological and chemical properties of the hybrid materials had been investigated by HRTEM, XPS, XRD and FTIR spectroscopy. Their optical properties will be presented. The preliminary results obtained on the conjugation of corroles onto the surfaces of ZnS nanocrystals will also be reported.

Acknowledgements: Thanks are due to FCT/MCTES for the financial support to CESAM (UID/AMB/50017/2019) and CICECO-Aveiro Institute of Materials (UID/CTM/50011/2019) through national funds, to the University of Aveiro and FCT/MCT for the financial support for the QOPNA research Unit (UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. This work was supported by the project [Corlutna (POCI-01-0145-031523)] funded by FEDER, through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI), and by national funds (OE), through FCT/MCTES. References: 1. J. F.B. Barata, M. G. P. M. S. Neves, M. A. F. Faustino, A.C. Tomé, J. A. S. Cavaleiro, Chem. Rev. 2017, 117, 3192. 2. J. F.B. Barata, A. Zamarrón, M. G. P.M.S. Neves, M. A. F. Faustino, A. C. Tomé, J. A. S. Cavaleiro, B. Röder, A. Juarranz, F. Sanz-Rodríguez Eur. J. Med. Chem. 2015, 92, 135. 3. J. F. B. Barata, A. L. Daniel-da-Silva, M. G. P. M. S. Neves, J. A. S. Cavaleiro, T. Trindade, RSC Advances 2013, 3, 274. 4. R. A. Pereira, T. S. Trindade, J. F. B. Barata Magnetochemistry, 2018, 4, 37-1.

Materials chemistry PC18

Displaying molecular interactions in ionic liquids through NMR Raquel V. Barrulas,a Mónica M. Lopes,a Tiago G. Paiva,a Marcileia Zanatta,a Marta C. Corvoa a

i3N|Cenimat, Departamento de Ciência dos Materiais, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, 2829-516 Caparica, Portugal Email: r.barrulas@campus.fct.unl.pt

Ionic liquids (ILs), organic salts with melting points below 100ºC, have been proposed as alternative solvents for extraction of natural compounds and carbon dioxide capture (CC) due to their stability, high selectivity and recyclability.1-6 The possibility of manipulating ILs properties – solvent polarity, acid/base character, density, viscosity, thermal stability – by tuning both cation/anion moiety to meet specific requirements has settled the potential for improved systems.3,4,7 Our work is focused on tailoring IL derived materials for specific purposes. Our approach relies on avoiding a slow process of trial and error through the study of interactions between ILs and model compounds. Therefore, we highlight the importance of nuclear magnetic resonance spectroscopy (NMR) to understand the molecular details of the interactions. The analysis of the ILs molecular interactions profile enables the selection and optimization of the cation/anion identity and their relation to solvated species.7 Diffusion experiments allow us to infer about the transport properties and aggregation behavior. Nuclear Overhauser effect (NOE) can be used to distinguish and quantify the intermolecular interactions (Figure 1). From these experiments, emerged the most successful IL structural features able to provide a solvent like behavior. This methodology allowed the rational development of alternative solvents for polyphenol compounds, CO2 capture and biopolymer dissolution, furthermore it may easily be extrapolated to a range of materials and applications.3,4,8

Figure 1: 2D 1H,1H-NOESY spectrum with 200 ms mixing time of [C4C1Im]Cl/naphthalene mixture [0.16:0.16 (M/M) in DMSO-d6] and main intermolecular interactions.7 Acknowledgements: This work was funded by National Funds through FCT – Portuguese Foundation for Science and Technology, reference UID/CTM/50025/2019 and FCT/MCTES, under the project PTDC/QUI-QFI/31508/2017, POR Lisboa and PTNMR (ROTEIRO/0031/2013;PINFRA/22161/2016), co-financed by FEDER through COMPETE 2020, Portugal, POCl, and PORL and FCT through PIDDAC (POCl-01-0145-FEDER-007688). References: 1. J. L. Anderson, J. K. Dixon, J. F. Brennecke, Acc. Chem. Res., 2008, 40, 1208–1216. 2. J. Dupont, Acc. Chem. Res., 2011, 44, 1223–1231. 3. M. C. Corvo et al., Chem.Sus.Chem., 2015, 8, 1935-1946. 4. R. V. Barrulas, T. G. Paiva, M. C. Corvo, Sep. Purif. Technol., 2019, 221, 29-37. 5. J. F. Brennecke, B. E. Gurkan, J. Phys. Chem. Lett., 2010, 1, 3459–3464. 6. B. Sreenivasulu, D. V Gayatri, I. Sreedhar, K. V Raghavan, Renew. Sustain. Energy Rev., 2015, 41, 1324–1350. 7. Mónica M. Lopes, Raquel V. Barrulas, Tiago G. Paiva, Ana S. D. Ferreira, Marcileia Zanatta and Marta C. Corvo (September 30th 2019). Molecular Interactions in Ionic Liquids: The NMR Contribution towards Tailored Solvents [Online First], IntechOpen, DOI: 10.5772/intechopen.89182. 8. T. Paiva, C. Echeverria, M. H. Godinho, P. L. Almeida, M. C. Corvo, Eur. Polym. J., 2019, 114, 353-360.

Materials chemistry PC19

Protein and alkaloids recover from lupine debittering leaching media João Afonso, Luísa M. Ferreira, Ana Lourenço LAQV-REQUIMTE, Faculty of Science and Technology, Universidade NOVA de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal Email: ana.lourenco@fct.unl.pt

Lupinus albus L. is a Portuguese endemic species that grows spontaneously under severe climate conditions. This Lupinus has high protein content, comparable to soybean, and is used as human food, and animal feed. (36-52% protein, 5-20% oil, 30-40% fiber).{Mohamed, 1995 #10} L. albus L. is bitter due to its content in quinolizidine alkaloids, whereas sweet species are imported from Australia and Chile. The culture of sweet lupine varieties is not feasible in Europe, where the bitter variety is prevalent. The bitter lupine alkaloids are toxic and their extraction is imperative before human consumption. The lack of adequate procedures for sustainable and profitable use of lupinus cultures in our country is yet to be solved. Different aqueous media were assayed for leaching process. Dicarboximethylcelulose (DCMC) designed and patented specifically to remove positively charged proteins from acidic beverages was produced from cellulose and 2bromomalonic acid.1 The ability of DCMC to discriminate between alkaloids and proteins, and the methods to assess the polymer ability to adsorb the lupine alkaloids present in a complex protein-containing blends will be presented.

Fig. 1 – Extraction of Lupinus albus L. in aqueous media.

Acknowledgements: We thank the Associate Laboratory for Green Chemistry- LAQV which is financed by national funds from FCT/MCTES (UID/QUI/50006/2019. The National NMR Facility supported by Fundação para a Ciência e Tecnologia (RECI/BBB-BQB/0230/2012). We acknowledge the Laboratório de Análises REQUIMTE for the technical support for the mass spectrometry analyses. References: 1. WO 2019/197884 A1. Ferreira, L.; Chagas, R.; Ferreira, R.B.; Coelhoso, I. Compound, method of production and uses thereof. 2019.

Materials chemistry PC20

Acetylated lignin nanoparticles: a potential photosensitizer vehicle for antimicrobial photodynamic therapy Nidia Maldonado-Carmona,a,b Mario J. F. Calvete,b Mariette M. Pereira,b TanSothea Ouk,a Nicolas Villandier,a Stephanie Leroy-Lheza a

University of Limoges, Laboratory PEIRENE, 87060, Limoges, France. bUniversity of Coimbra, Department of Chemistry, 3004-535, Coimbra, Portugal Email: nidia.maldonado@etu.unilim.fr

Lignin is the second most abundant natural polymer. It is a side-product from the paper industry and it is estimated that around 10 millions tons are produced each year, from which up to 98% is burnt for energy production.1 Currently, there is an increase of lignin applications on medicine and pharmaceutics, specially as a transport of small non-polar molecules.2,3 improving their accumulation on targeted tissues. Antimicrobial PhotoDynamic Therapy (APDT) relies on the inactivation of bacteria through the concomitant presence of light, oxygen and a photosensitizing molecule (PS), for reactive oxygen species generation. Despite its several advantages, some of the major limitations of APDT is the low aqueous solubility of PS, which inhibits their usage on medical applications.4,5 Aiming to produce systems that may improve delivery of PS, we present here the synthesis of acetylated lignin nanoparticles (@AcLi) and successful encapsulation of several PS molecules.

Figure 1. Compounds succesfully encapsulated inside @AcLi

Furthermore, these nanoparticles were tested against the bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus aureus and Enterococcus faecalis, where we found the best results were found with TPPOH@AcLi nanoparticles against Gram positive bacteria S. epidermidis, S. aureus and E. faecalis, under white LED light irradiation (148 J/cm2). TPPOH@AcLi demonstrated lower singlet oxygen production and an increase at the minimal inhibitory concentration necessary to eradicate 99.9% of bacteria, when compared with non-immobilized TPPOH. TPPOH@AcLi also demonstrated an increased photostability and stability, without compound leaching up to 60 days. Also, it was demonstrated that TPPOH@AcLi tends to surround and aggregate bacteria, a characeristic that it is nowadays investigated for water decontamination. In conclusion, acetylated lignin nanoparticles are suitable vehicles for photosensitizing molecules. Further investigation is carried away against planktonic Gram negative bacteria and biofilm. Acknowledgements: This project was financed through an European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement n°764837. References: 1. S. Beisl, A. Friedl, and A. Miltner, Int. J. Mol. Sci., 2017, 18, 2367. 2. G. Marchand, C. A. Calliste, R. M. Williams, C. McLure, S. Leroy-Lhez, and N. Villandier, ChemistrySelect, 2018, 3, 5512. 3. M. Witzler, A. Alzagameem, M. Bergs, B. El Khaldi-Hansen, S. E. Klein, D. Hielscher, B. Kamm, J. Kreyenschmidt, E. Tobiasch, and M. Schulze, Molecules, 2018, 23, 1. 4. M. Q. Mesquita, C. J. Dias, M. P. M. S. Neves, A. Almeida, and M. F. Faustino, Molecules, 2018, 23, 2424. 5. R. T. Aroso, M. J. F. Calvete, B. Pucelik, G. Dubin, L. G. Arnaut, M. M. Pereira, and J. M. Dąbrowski, Eur. J. Med. Chem., 2019, 184, 111740. 6. P. Figueiredo, K. Lintinen, A. Kiriazis, V. Hynninen, Z. Liu, T. Bauleth-Ramos, A. Rahikkala, A. Correia, T. Kohout, B. Sarmento, J. Yli-Kauhaluoma, J. Hirvonen, O. Ikkala, M. A. Kostiainen, and H. A. Santos, Biomaterials, 2017, 121, 97.

100

Materials chemistry PC21

Evaluation of growth inhibition effect of free and nanoincorporated xanthone derivative on a human breast cancer cell line Maribel Teixeira,a Madalena Pedro,a Maria São José Nascimento,b Madalena M. M. Pinto,c,d Carlos Maurício Barbosae a

CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Gandra PRD, Portugal. bLaboratory of Microbiology, Department of Biological Sciences, cLaboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, dInterdisciplinary Centre of Marine and Environmental Research, University of Porto, Matosinhos, Portugal. eLaboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. E-mail: mauricio.barbosa@ff.up.pt

Introduction:In a previous work, the effect of nanoparticulate formulations containing 1,3dihydroxy-2-methylxanthone (DHMXAN) on the growth of the human breast cancer cell line MCF-7 was studied using the sulforhodamine B (SRB) assay.1 This colorimetric protein assay method estimates cell number indirectly by staining cellular protein with a protein-binding dye. The incorporation of DHMXAN in nanospheres and nanocapsules afforded a marked potentiation of the compound inhibitory effect. Through the SRB assay the inhibition of growth of the initial cell population was measured. Nevertheless, SRB assay does not measure cell viability but its protein content. Therefore, some measured proteins by the assay may come from cells that are not viable. In order to clarify the nature of the effect of free and nanoincorporated DHMXAN on MCF-7 cells, in the present work the cell viability was studied through the MTT assay, which measure specifically metabolically active cells, giving more accurate information than the SRB method on cytotoxicity. Materials and Methods Preparation and characterization of nanoparticle formulations: DHMXAN-loaded and empty nanoparticles (nanospheres and nanocapsules) were prepared by the solvent displacement technique and characterized regarding particle size, zeta potential, DHMXAN content and incorporation efficacy, as described elsewhere.1 Cell viability assay: The effect of free and nanoicorporated DHMXAN on viability of MCF-7 cell line was evaluated in vitro using the MTT assay.2 Cell viability (%) was determined comparing viability of cells treated with formulations to that corresponding to non-treated control cells. Results and Discussion: In comparison with free compound, DHMXAN-loaded nanocapsules afforded a significant decrease in cell viability (P <0.05) for most tested concentrations (6, 13, 52 and 103 μM). Regarding DHMXAN-loaded nanospheres, cell viability decrease was higher only for the lowest concentrations (6 μM, 13 μM; P <0.05), exhibiting a similar effect to the free compound at the other concentrations. Empty nanocapsules and nanospheres showed a cytotoxic effect at concentrations higher than 52 μM and 26 μM, respectively (Fig. 1).

Fig. 1 – In vitro evaluation of nanoparticulate DHMXAN formulations

Conclusions: The increased potentiation of in vitro cytotoxic effect of DHMXAN incorporated in nanocapsules, comparing to nanospheres, may lead to the conclusion that nanocapsules are more suitable for the vectorization of this xanthone. In addition, the observed lower cellular toxicity of empty nanocapsules compared to nanospheres also suggests that the latter carrier is more suitable for the delivery of DHMXAN. Acknowledgments: This work was partially supported through national funds provided by FCT/MCTES - Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE – Programa Operacional Factores de Competitividade (POFC) programme, under the Strategic Funding UID/Multi/04423/2013, and the project PTDC/MAR-BIO/4694/2014 (ReferencePOCI-01-0145-FEDER-016790; Project 3599, Promover a Producão Científica e Desenvolvimento Tecnológico e a Constituicão de Redes Temáticas (3599-PPCDT)), in the framework of the programme PT2020. References 1. M. Teixeira, M. Pedro, M.S.J. Nascimento, M.M.M. Pinto, C.M. Barbosa, Pharm. Dev. Technol. 2019, 24, 1104. 2. T. Mosmann, J. Immunol. Methods 1983, 65, 55.

101

Materials chemistry PC22

Chitosan hydrogel polymer bases with potential application in veterinary medicine Marina Costa,a Mara Silva,b Isabel Campos-Gonçalves,b Cesar Filho,b Alexandre C. Craveiro,b Elisabete P. Carreiro,a António P. S. Teixeira,a,c Anthony J. Burkea,c a

Centro de Química de Évora, IIFA, School of Science and Technology, University of Évora, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal. bBRinova - Bioquímica, Lda, Rua Fernanda Seno, 6, 7005-485 Évora, Portugal. cDepartment of Chemistry, University of Évora, School of Science and Technology, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal. Email:marinamcosta91@gmail.pt

Hydrogels are physically or chemically cross-linked three-dimensional polymer networks with a large number of hydrophilic groups, capable of absorbing large amounts of water.1 Chitosan is a natural polymer obtained from the deacetylation of chitin and has biocompatibility, biodegradability, mucoadhesiveness, antimicrobial and hemostatic properties including the ability to accelerate wound healing by modulating the function of inflammatory cells.2,3 An important advantage of using chitosan is its biodegradation, which occurs mainly under the action of tissue enzymes, that leads to non-toxic by-products that are easily excreted.2 Over the past 40 years it has been widely used in medicine, and most research has described its use in wound care, serving as biomaterial for tissue engineering with possible veterinary applications.4 In this communication we will describe the characterization of chitosan-based hydrogels through various techniques such as scanning electron microscopy (SEM) (morphology assessment), Fourier transform infrared spectroscopy with attenuated total reflectance (FTIR-ATR) (composition assessment), including swelling tests (assessment of wetting capacity). Figure 1(A) shows the infrared (IR) spectra of chitosan based hydrogel, exhibiting the following characteristic bands: 3408 cm-1 (presence of the OH group), 2926 cm-1 (CH2 asymmetric stretching), 1638 cm-1 (stretching C=O), 1022 cm-1 (axial deformation C-O). The micrograph obtained by SEM (Figure 1(B)) shows various pore structures. Also, the swelling behavior show the capacity to be adjusted by changing the chitosan contents. This results clearly suggested the success of chitosan-based hydrogel synthesis that could be a suitable for the veterinary use, with potential to ensure skin tissue growth. A)

Figure 1. FTIR spectrum (A) and SEM image (B) (200×) of chitosan-based hydrogel. Acknowledgements: We thank to the project “NAQUIBIODPSA obtenção de medicamentos veterinários a partir de nanopartículas de prata fixadas em bases poliméricas de hidrogéis de quitosana”, with reference ALT20-03-247-FEDER-033578 co-financed by the ERDF through the Alentejo Regional operational program, through COMPETE-Programa Operacional Fatores de Competitividade (POFC). Project co-financed by the European Union Fund. We also thank the FCT for financial support through project UID/QUI/0619/2019-CQEUE. References: 1. F. A. Fookes, L. N. Mengatto, A. Rigalli, J. A. Luna, Journal of Drug Delivery Science and Technology, 51, 2019, 268-275. 2. A. M. Craciun, L. M. Tartau, M. Pinteala, L. Marin, Journal of Colloid and Interface Science, 536, 2019, 196207. 3. S. Senel, S. J. McClureb, Advanced Drug Delivery Reviews, 56, 2004, 1467-1480. 4. O. Drewnowska, B. Turek, B. Carstanjen, Z. Gajewski, Polish Journal of Veterinary Sciences, 16, 2013, 843–848.

102

Natural product chemistry PC23

Structure and toxicity of STX-group toxins Joana F. Leala, M.L.S. Cristianoa,b a Centre of Marine Sciences (CCMAR) – University of Algarve, Campus de Gambelas 8005-139 Faro, Portugal. bDepartment of Chemistry and Pharmacy, Faculty of Science and Technology – University of Algarve, Campus de Gambelas 8005-139 Faro, Portugal Email: jfleal@ualg.pt; mcristi@ualg.pt

The number of harmful algae bloom (HAB) episodes has increased, mainly potentiated by environmental and climatic conditions, eutrophication and also as consequence of the anthropogenic activities.1 These natural phenomena are characterized by a massive growth of phytoplankton in marine ecosystems, able to produce highly toxic natural toxins, called phycotoxins or marine biotoxins,2 that cause great social and economic concern. These toxins bio-accumulate in aquatic species, namely bivalves, through the food chain, and may be potentially toxic for humans, depending on the levels ingested. Based on the toxic effects they cause, four groups can be defined, namely, paralytic shellfish poisoning (PSP), amnesic shellfish poisoning (ASP), neurotoxic shellfish poisoning (NSP) and diarrhetic shellfish poisoning (DSP). Data from 1980 to 20153 revealed that 35.5 % of the toxic events were due to PSP. This group of toxins is headed by saxitoxin (STX) and is especially worrying because it can cause death in less than 4 hours.4 Depending on the R4 substituent (Figure 1), STXgroup toxins may be clustered into different subgroups, including the carbamate, Nsulfocarbamoyl and decarbamoyl ones. Some structure-activity studies are available, but most of them are old (with over 20 years) and with difficult access. Thus, we aim to contribute through an update and further elucidation regarding structure and toxicity in STX-group toxins. With this purpose in view, this study presents a compilation of the main interconversion reactions that occur between the different molecules of the STX-group in view of relating structural differences with changes in toxicity. Many interconversion reactions, such as reductive conversion, hydrolysis, enzymatic conversion and/or epimerization may occur in organisms. In general, the conversion of N-sulfocarbamoyl into carbamate toxins is known to increase toxicity, while the epimerization (β to α) appears to decrease toxicity.5

Figure 1: Molecular structure of STX-group toxins (resonance structure representation). Acknowledgements: This study received support by Portuguese national funds from FCT – Foundation for Science and Technology through project UID/Multi/04326/2019. Joana F. Leal acknowledges CCMAR for a postdoctoral fellowship (CCMAR/SC/BPD/29/2019). References: 1. F. Farabegoli, L. Blanco, L. P. Rodríguez, J. M. Vieites, A. G. Cabado, Mar. Drugs 2018, 16(6), 188. 2. H. P. v. Egmond, Anal Bioanal Chem. 2004, 378, 1152. 3. I. Sanseverino, D. Conduto, L. Pozzoli, S. Dobricic, T. Lettieri, JRC Technical Reports, 2016, 52. 4. C. Garcı́a, M. a. del Carmen Bravo, M. Lagos, N. Lagos, Toxicon 2004, 43(2), 149. 5. S. Hall, G. Strichartz, E. Moczydlowski, A. Ravindran, P. B. Reichardt, ACS Symposium Series 1990, 418, 29.

103

Natural product chemistry PC24

Evaluation of the antioxidant activity of curcumin and piperine extracts, and their combination, in in vitro cellular and noncellular systems Mariana Lucas,a Daniela Ribeiro,a Marisa Freitas,a Fabiana Moura,b Jadriane Xavier,c Marília Goulart,c Eduarda Fernandesa a LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. b Postgraduation Program of Nutrition (PPGNUT), Nutrition Faculty, Federal University of Alagoas (FANUT/UFAL), Brazil. c Institute of Chemistry and Biotecnology, Federal University of Alagoas (IQB/UFAL), Brazil. Email: mariana_lucas1994@hotmail.com

The body has several antioxidant defense mechanisms that fight oxidative stress, defined as an imbalance between the production of reactive prooxidant species and the organism’s capacity to counteract them by its antioxidant systems. Oxidative processes are known to be implicated in various diseases as cancer, inflammatory diseases or even in ageing. Curcumin (Figure 1A) is a polyphenol from the rhizome of Curcuma longa that has has been shown to have therapeutic potential, e.g. as anti-inflammatory and anti-diabetic.1 Piperine (Figure 1B) is the most abundant alkaloid in pepper, Piper nigrum L. Several studies indicate that piperine has also interesting biological properties. Recently, it was reported that the combination of curcumin with piperine increases the biological potential of these compounds, including their bioavailability.2 The purpose of the present study was to evaluate and compare the putative scavenging of reactive oxygen and nitrogen species by curcumin and piperine extracts per se and also in combination, using in vitro non-cellular systems. In addition, the modulation of human neutrophis’ oxidative burst was evaluated, using luminol as probe.3 The obtained results show that curcumin extract exhibits a concentration-dependent scavenging effect for hypochlorous acid and nitric oxide, with IC50 values of 0.25 ± 0.01 µg/mL and 1.51 ± 0.11 µg/mL, respectively, while no scavenging effect against superoxide anion radical was found in our tested experimental conditions. The combination of both extracts presented similar results to these ones. In turn, piperine extract exhibited no scavenging effect, under the tested experimental conditions. Interestingly, curcumin extract was also able to inhibit luminol oxidation (IC50 of 0.54 ± 0.05 µg/mL). Once again, piperine was not active and the combination of both extracts produced results similar to the ones obtained using the curcumin extract alone. In conclusion, curcumin extract has shown effective antioxidant activity in both non-cellular and cellular assays. In contrast, piperine extract did not show any effect in the performed assays. Finally, the combination of the two extracts had the same effect as curcumin, showing neither synergistic nor antagonistic antioxidant activity, indicating that the beneficial effects may result from their in vivo interaction, probably at a pharmacokinetic level.

Figure 2: Chemical strutures of curcumin (A) and piperine (B).1,2 Acknowledgements: This work received financial support from PT National funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through grant UID/QUI/50006/2019 and from Brazilian agencies Healthy Ministery/PPSUS/FAPEAL and CNPq (grant 435703/2018-4). References: 1. A. Noorafshan, S. Ashkani-Esfahani, Curr. Pharm. Des. 2013, 19, 2032-2046. 2. G. Shoba, D. Joy, T. Joseph, M. Majeed, R, Rajendran, P. S. S. R. Srinivas, Planta Med. 1998, 64, 353-356. 3. A. Gomes, D. Couto, A. Alves, I. Dias, M. Freitas, G. Porto, J. A. Duarte, E. Fernandes, Biofactors 2012, 38, 378-386.

104

Natural product chemistry PC25

Biomass valorization: methanolysis of oleuropein Lídia A. S. Cavaca,a Catarina A. B. Rodrigues,a Svilen P. Simeonov,a,b Rafael F. A. Gomes,a Jaime A. S. Coelho,a Gustavo P. Romanelli,c Angel G. Sathicq,c José J. Martínez, d Carlos A. M. Afonsoa a Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal; b Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences. Acad. G. Bonchev str., bl. 9, 1113, Sofia, Bulgaria; c Centro de Investigación y Desarrollo en Ciencias Aplicadas “Dr. J.J. Ronco” (CINDECA), Departamento de Química, Facultad de CienciasExactas Universidad Nacional de la Plata Argentina Calles 47 Nº 257, B1900 AJK, La Plata, Argentina; d Escuela de Ciencias Químicas, Facultad de Ciencias, Universidad Pedagógica y Tecnológica de Colombia UPTC; Avenida Central del Norte, Tunja, Boyacá, Colombia

Email: l.cavaca@ff.ulisboa.pt

Oleuropein is one of the major secoiridoids found in the olive leaf (0.5-2% (w/w) on dry basis).1 Oleuropein structure can be divided in three subunits – glucoside, monoterpene and hydroxytyrosol (red, black and blue, respectively, Figure 1).2 The monoterpene unit is a highly functionalized moiety that includes two esters, one alkene, one enol ether, one acetal and a stable chiral center at C-4. This multifunctional structure makes it difficult to be obtained by other means than extraction from natural sources.3 In this context, we became interested in the valorization of oleuropein towards the synthesis of diverse and synthetically rich building blocks. The acid-promoted methanolysis of oleuropein was studied using a variety of homogeneous and heterogeneous acid catalysts. Exclusive cleavage of the acetal bond between the glucoside and the monoterpene subunits or further hydrolysis of the hydroxytyrosol ester and subsequent intramolecular rearrangement were observed upon identification of the most efficient catalyst and experimental conditions. Furthermore, selected conditions were tested using Oleuropein under continuous flow and using a crude mixture extracted from olive leaves under batch. Formation of (-)-methyl elenolate was also observed in this study, which is a reported precursor for the synthesis of the antihypertensive drug (-)-ajmalicine.4

Figure 1: Tunable acid-promoted methanolysis of oleuropein. Acknowledgements: The authors acknowledge Fundação para a Ciência e a Tecnologia (FCT) (refs UID/DTP/04138/2013, SFRH/BPD/100433/2014, SFRH/BPD/109476/2015 PD/BD/128316/2017), COMPETE Programme (SAICTPAC/0019/2015) and European Research Area Network; ERANet LAC (ref ELAC2014/BEE0341) for financial support.

References: 1. M. L. de Castro, R. Japón-Luján, Trends Anal. Chem. 2006, 25, 501. 2. Z. Erbay, F. Icier, Food Rev. Int. 2010, 26, 319. 3. L. A. S. Cavaca, C. A. M. Afonso, Eur. J. Org. Chem. 2018, 2018, 581. 4. L. A. S. Cavaca et al. ChemSusChem, 2018, 11(14), 2300.

105

Natural product chemistry PC26

Flavonoids versus chalcones: which are the most efficient inhibitors of key digestive enzymes in the management of diabetes mellitus? Marisa Freitasa, Sónia Rochaa, Carina Proençaa, Daniela Ribeiroa, Alberto N. Araújoa, Artur M.S. Silvab, Eduarda Fernandesa a LAQV-REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. b LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. Email: marisafreitas@ff.up.pt

Diabetes mellitus is one of the most prevalent metabolic diseases worldwide, characterized by the excessive accumulation of free glucose in blood. A possible therapeutic approach to decrease the postprandial hyperglycemia is to retard the absorption of glucose through the inhibition of α-amylase and α-glucosidase enzymes involved in the digestion of carbohydrates by hydrolyzing α-(1,4)-glycosidic bonds. Therefore, inhibitors of these enzymes can be an important strategy in the management of type 2 diabetes.1 Chalcones are secondary metabolites of terrestrial plants and are considered precursors of flavonoids biosynthesis. Chalcones and flavonoids are recognized for their multiple biological activities, including anti-diabetic effects.2,3,4 Thus, our aim was to compare the inhibitory effect of a panel of both groups of compounds, against α-amylase and α-glucosidase activity. For that purpose, an in vitro spectrophotometric technique was used, by measuring the α-glucosidase-mediated transformation of the substrate p-nitrophenyl-α-D-glucopyranoside (pNPG) into pnitrophenol; and the α-amylase-mediated transformation of 2-chloro-p-nitrophenyl-α-Dmaltotrioside (CNPG3) into 2-chloro-p-nitrophenol. It was possible to conclude that, in general, flavonoids were more active than their respective precursor chalcones. Moreover, the obtained results show that both groups of compounds were selective inhibitors for αglucosidase activity, with IC50 values lower than the obtained for the currently used drug, acarbose. Potentially effective compounds were found in this work and should be further studied and improved to be used as alternatives to the commonly prescribed inhibitors of the carbohydrate hydrolyzing enzymes.

Acknowledgements: This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through grant UID/QUI/50006/2019, and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI-01-0145-FEDER-029241). Carina Proença and Sónia Rocha acknowledge FCT the financial support for the PhD grant (SFRH/BD/116005/2016 and PD/BD/145169/2019, respectively), in the ambit of "QREN POPH - Tipologia 4.1 - Formação Avançada", co-sponsored by Fundo Social Europeu (FSE) and by national funds of Ministério da Ciência, Tecnologia e Ensino Superior (MCTES).

References: 1. S. Rocha, D. Ribeiro, E. Fernandes, M. Freitas, Curr. Med. Chem. 2018, 25. 2. S. Rocha, A. Sousa, D. Ribeiro, C. M. Correia, V. L. M. Silva, C. M. M. Santos, A. M. S. Silva, A. N. Araújo, E. Fernandes, M. Freitas, Food Funct. 2019, 10. 3. C. Proença, M. Freitas, D. Ribeiro, E. F. T. Oliveira, J. L. C. Sousa, S. M. Tomé, M. J. Ramos, A. M. S. Silva, P. A. Fernandes, E. Fernandes, J. Enzyme Inhib. Med. Chem. 2017, 32. 4. C. Proença, M. Freitas, D. Ribeiro, S. M. Tomé, E. F. T. Oliveira, M. F. Viegas, A. N. Araújo, M. J. Ramos, A. M. S. Silva, P. A. Fernandes, E. Fernandes. J. Enzyme Inhib. Med. Chem. 2019, 34.

106

Natural product chemistry PC27

The promising effect of flavonoids in type 2 diabetes therapy: inhibition of key enzymatic targets with a significant role in the development of hyperglycaemia Carina Proença,a Marisa Freitas,a Daniela Ribeiro,a Sara M. Tomé,b Artur M. S. Silva,b Pedro A. Fernandes,c Eduarda Fernandesa a

LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. b LAQV, REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. c UCIBIO, REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169007 Porto, Portugal.

Email: up201302568@ff.up.pt

Type 2 diabetes (T2D) is a growing health problem, currently affecting around 463 million adults worldwide. The therapeutic approach for T2D is frequently associated with multiple adverse effects, often leading to incompliance and treatment failure. Thus, the search and development of new antidiabetic agents with a good safety profile has been a long-lasting need. Flavonoids are wellrecognized phenolic and heterocyclic compounds widely distributed in nature. As that flavonoids have been demonstrating potential antidiabetic properties1,2,3,4, the present work aimed to evaluate the structure-activity relationship concerning the inhibitory activity of flavonoids against several enzymes involved in hyperglycaemia - α-glucosidase, α-amylase, protein tyrosine phosphatase 1 B (PTP1B), dipeptidyl dipeptidase-4 (DPP-4) and fructose 1,6-bisphosphatase (FBPase). A panel of 30 flavonoids was tested, some of them for the first time. The enzyme-catalyzed hydrolysis of the substrate (selected according to each of the mentioned enzymes) was measured by monitoring the absorbance or fluorescence signal of the generated product. The obtained results suggest that the hydroxylation of flavonoids at 7- and 8- positions of A ring, at 3’- and 4’-positions of B ring and at 3-position of C ring (competitive inhibitior), is crucial for the inhibition of α-glucosidase. For the inhibition of α-amylase, a flavone with -OH groups at 5- and 7-positions of A ring and at 3’- and 4’-positions of B ring, together with a -Cl substituent at 3-position of C ring (competitive inhibitor) was the most active among the tested flavonoids. Concerning PTP1B inhibition, the presence of -OBn groups at 7- and 8-positions of A ring, together with the presence of -OMe groups at both 3'- and 4'-positions of B ring and the -OH group at 3-position of C ring (mixed type inhibitor), has shown to be favourable for the intended effect. Regarding the inhibitory effect against DPP-4, the most active flavonoid indicates that the presence of -OH groups at 7- and 8-positions of A ring and at 3position of C ring, together with the presence of -OMe groups at 3’- and 4’-positions of B ring (noncompetitive inhibitor) increases the inhibition of the enzyme, in comparison to the other studied flavonoids. Finally, baicalein was the best inhibitor of FBPase, revealing that the hydroxylation at 5-, 6and 7-positions of A ring has an important role for this specific biological effect. The obtained results allowed the establishment of an accurate structure-activity relationship and the disclosure of the most important substituents in the flavonoid scaffold for the modulation of each therapeutic target under study. This study will certainly contribute for the development of new flavonoidbased molecules with improved antidiabetic activity, and with potential to be used as alternative options to the conventional agents available for the treatment of T2D. Acknowledgements: This work was supported by UID/QUI/50006/2019 with funding from FCT/MCTES through national funds, and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI-01-0145-FEDER-029241). Carina Proença acknowledges FCT the financial support for the PhD grant (SFRH/BD/116005/2016), in the ambit of "QREN - POPH - Tipologia 4.1 - Formação Avançada", co-sponsored by Fundo Social Europeu (FSE) and by national funds of Ministério da Ciência, Tecnologia e Ensino Superior (MCTES). References: 1. C. Proença, M. Freitas, D. Ribeiro, E. F. T. Oliveira, J. L. C. Sousa, S. M. Tomé, M. J. Ramos, A. M. S. Silva, P. A. Fernandes, E. Fernandes, J. Enzyme Inhib. Med. Chem. 2017, 32(1), 1216-1228. 2. C. Proença, M. Freitas, D. Ribeiro, J. L. C. Sousa, F. Carvalho, A. M. S. Silva, P. A. Fernandes, E. Fernandes, Food Chem. Toxicol. 2018, 111, 474-481 3. C. Proença, M. Freitas, D. Ribeiro, S. M. Tomé, E. F. T. Oliveira, M. F. Viegas, A. N. Araújo, M. J. Ramos, A. M. S. Silva, P. A. Fernandes, E. Fernandes, J. Enzyme Inhib. Med. Chem. 2019, 34, 577-588. 4. C. Proença, M. Freitas, D. Ribeiro, S. M. Tomé, A. N. Araújo, A. M. S. Silva, P. A. Fernandes, E. Fernandes, Food Funct. 2019, 10(9), 5718-5731.

107

Natural product chemistry PC28

Application of hydralcoholic extracts of Salvia officinalis and Salvia elegans in cosmetic formulations Yonah Faveroa,e, Laryssa da Silvab, Daiana Santos de Almeidac, Olivia Pereirad,e, M.J.Sousad,e a

Federal university of Goiás- Jatobá Campus-University City, BR 364, km 195, nº 3800 CEP 75801-615. bState University of Feira de Santana - Avenida Transnordestina, s/n - Novo Horizonte CEP 44036-900 - Feira de Santana – Bahia. cFederal Institute of Rio de Janeiro, 88 Pereira de Almeida street, Flag Square, Rio de Janeiro, RJ, ZIP Code: 20260-100. dMountain Research Center, Bragança Polytechnic Institute, Campus Santa Apolónia, Aparteda 117, 5301-855 Bragança, Portugal. e Bragança Polytechnic Institute- Agraria de Bragança Highter School.

Email: joaos@ipb.pt

Salvia Officinalis and Salvia elegans are shrubs belonging to the genus Salvia, family of the Lamiaceae, easily found in the Mediterranean region, Mexico and Guatemala respectively. In addition to traditional medicine, S. officinalis is of great importance to the pharmaceutical, cosmetic and food industries. (Cuvelier et al., 1996; Martins et al., 1998 in Povh & Ono, 2008), whereas S. elegans is known in cooking as a preservative or flavoring (Pereira et al., 2014). Natural products have increased, discovering new therapeutic indications, meeting the demands of the world population taking into account their quality and safety. In this study, the focus is on phenolic compounds as an active ingredient in an anti-age formulation. Carbopol and methylcellulose-based gel was prepared together with Salvia officinalis and Salvia elegans hydroalcoholic extract as their active principle by performing physical-chemical, organoleptic gel stability tests and performing the eye irritability test (HET-CAM), beyond performing hydrodistillation at Clevenger. The essential oil was extracted by steam entrainment, yielding after 3 hours. The hydroalcoholic principle gels were prepared at three different concentrations, 1.25; 2.5 and 5%, and then tests were performed to evaluate the stability of the product obtained as: light cycles, freeze / thaw cycles, centrifugation and vortexing, pH determination, microbiological analysis and HET-CAM test. According to the results, the pH test showed changes for the two plants containing their gels but never exceeding the ideal limits for the skin, even when exposed to the light cycle, only the color that was changed after 15 days, in the different concentrations. In freezing / thawing tests for Salvia officinalis the methylcellulose gel did not change, the carbopol gel did change the appearance but small changes are acceptable as the samples are subjected to extreme heat (45 ° C) and cold temperatures. (-20 ° C). For Salvia elegans there was a change in appearance and pH, which was also changed in the methylcellulose gel. All pH changes do not lead to considerer the gel as inappropriate. In microbiological tests the oils have a moderate effect, while in the other tests there were no changes. Centrifugation and vortex tests were performed for both gels using both plants with only hydroalcoholic extract at different concentrations and there was no change. All gels had an alcoholic odor during the tests. It can be concluded that carbopol and methylcellulose gel do not appear to have any detrimental effects when used in this cosmetic product, even when used in conjunction with plant essential oil and can therefore be used as an anti-aging formulation. However, the development of more tests is extremely important as toxicity tests, but stability tests already have promising results. Acknowledgements: The authors thank the Science and Technology Foundation (FCT, Portugal) and the ERDF under the PT2020 Program for their financial support to CIMO (UID / AGR / 00690/2019) References: 1.Pereira, Olivia R .; Afonso, Andrea F .; Silva, Joana de A.; Batista, Ana Rita; Sobral, Abílio J. F. N .; Cardoso, Susana M. (2014). Salvia elegans: A natural source of antioxidant compounds. In XII Food Chemistry Meeting. Lisbon 2. Povh, J. A., & Ono, E. O. (November 2008). Growth of Salvia officinalis plants under action of plant growth regulators. Rural Science, 38, 2186-2190.

108

Natural product chemistry PC29

Study of antagonistic interaction of extracts of Banisteriopsis laevifolia (A.Juss) B. Gates against Magnaporthe oryzae Carla T. P. Coelho,a Maria I. de S. C. Silva,a Jorge L. S. Simão,a Leila G. de Araújo,b Vanessa G. P. Severinoa a

Natural Products and Organic Synthesis Laboratory, Chemistry Institute, Federal University of Goiás.CEP Goiânia, Brasil. b Laboratory of Genetic of Microorganisms, Biological Science Institute, Federal University of Goiás.CEP Goiânia, Brasil

Email: carlathaispc19@gmail.com

The Brazilian tropical savannah known as Cerrado, has one of the biggest diversity of flora in the world1. This biome is found mainly in the central region of the country, where the Malpighiaceae family is easily detected2. The genus Banisteriopsis, belonging to this family, has been investigated due to its potential applications, there are several reports of antimicrobial, anti-inflammatory, antipyretic and antifungal activity in the literature3.The specie B. laevifolia (A. Juss.) B. Gates, belonging this genus, is popularly known as 'cipó-prata' and had its leaves studied by Nunes et al., 20154, and demonstrated relevant antifugistatic potential. Rice, Oryza sativa L., one of most import cereal for the world population, often suffers from the attack of pests. The fungus Magnaporthe oryzae, responsible for the disease called brusone, is common to this crop, and causes big losses of productivity5. Nowadays, the synthetic chemical pesticides are widely used; but they are potentially toxics, so it is important to research for safer substances that can be incorporated into production systems that seek sustainability with less environmental impact, through natural compounds applied to crops6. Thus, in this study, the leaves and flowers ethanolic extracts of B. laevifolia was analyzed, which inhibit the growth of M. oryzae; For the development of the study, mycelium discs of the pathogen was inserted in glass plate containing the culture medium composed of potato, dextrose and agar (PDA) plus the extracts of the plant, which was tested in four different concentrations: 0,25;0,50;0,75;1,00 mg.mL -1. The analyses were made daily, and for nine days, using an caliper. With the collected data, the statistical treatment of each essay was performed (Table 1). Control

0,25 mg

0,50 mg

0,75 mg

1,00 mg

Extract of Flower

-A

5,25 B

9,87 BC

14,37 C

30,41 D

Extract of Leaves

-A

2,45 A

9,51 B

12,36 B

21,72 C

Table 1: Statistical parameters of reduction of the area of the colony of M. oryzae in contact with the ethanolic extracts of the leaves and flowers of B. laevifolia. Note: values are expressed in area averages (mm).

The concentrations of 0.75 and 1.00 mg.mL -1 of the flowers had a better mycelial reduction. Other evidence of this, was the observation of an whitish coloration of the pathogen during its growth in the extracts, what indicate a non-production of the dark melanin by the M. oryzae, fundamental to maintaining the life of the fungi7. Then, the ethanolic extract of the flowers, which showed the best result, was fractionated using hexane, dichloromethane, ethyl acetate, n-butanol and water. In addition, it was submitted to the analysis of the chemical profile by Liquid Chromatography coupled to Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR). Through the results, we noticed the presence of phenolic compounds in it, which may be related to the fungistatic activity observed8,9. In conclusion, considering the fungistatic activity of ethanolic extracts of B. laevifolia against M. oryzae analyzed and quantified in this study, suggest possibility for the control of this pests with a natural product. Acknowledgements: The authors gratefully thank to the Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for the financial support for this research. References: 1. Oliveira-Filho, A. T., and J. A. Ratter, Columbia University Press, New York, 2002, 91-120. 2. ANDERSON, W.R., Mem. N. Y. Bot. Gard. 1990, v. 64, 210–224. 3. FREITAS, L. B. O, et al. Phytochemistry Letters, Amsterdam, 2015, v. 12, 9-10. 4. NUNES, B. C, et al. Industrial Crops and Products, 2016, 92, 277-289. 5. RAY M. et al, Biosensors and Bioelectronics, 2017, v. 87, 708-723. 6. BARRADAS, L. P. et al, Pesquisa Agropecuária Tropical, 2015, 45, n. 1, 29-38. 7. BERTOLAZI, A. A., Tese (Doutorado em Produção Vegetal), 2016. 8. MIRÓN-MÉRIDA , V. A., et al , LWT, 2019, v. 101, 167-174. 9. SALAS, M. P., et al. Food Chemistry, 2011, v. 124, Issue 4, 1411-1415.

109

Natural product chemistry PC30

Valorization of sugars from the eucalypto wood liquefaction process L. B. Silva,a,b,c R. Galhano dos Santos,c J. C. Bordado,c P. Pinto,d A. P. Rautera,b a Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa. bCentro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa. cCentro de Recursos Naturais e Ambiente, Instituto Superior Técnico, Universidade de Lisboa. dRAIZ- Forest and Paper Research Institute,Quinta de S. Francisco, Apartado 15, 3801-501 EIXO, Portugal.

Email: lbsilva@fc.ul.pt

Studies on the liquefaction of eucalyptus wood residues show that eucalyptus sawdust / sawdust comprises 41% cellulose, 31% hemicellulose, 29% acid-insoluble lignin and 5.1% sugars.1 However, the fraction composed by sugars has not been studied and they have not been characterized,2 making it important to study and value these sugars aiming at greater process sustainability, as well as the formation of new molecules from these sugars. The valorization of sugars from eucalyptus biomass may serve as a low cost alternative for the pharmaceutical and agro-industry, as well as for the production of compounds with antioxidant potential, which are essential in the production of several products / drugs. The main objective of this work is to study the valorization of the sugars present in the aqueous fraction from the eucalyptus biomass liquefaction processes, allowing its use as a starting material for the synthesis of new compounds, and in industrial or agro-industrial production processes. Therefore, this study is of great relevance because although there are some studies on the process of liquefaction of eucalyptus biomass, the methodologies applied have not yet been sufficient to elucidate the characteristics of mixtures resulting from liquefaction and the structure of sugars originated during this process.3 Moreover, there are still no synthetic routes leading to the formation of new molecules using sugars from the liquefaction of eucalyptus wood as a starting material. Acknowledgements: This work was carried out under the Project inpactus – innovative products and technologies from eucalyptus, Project N.º 21874 funded by Portugal 2020 through European Regional Development Fund (ERDF) in the frame of COMPETE 2020 nº246/AXIS II/2017. References: 1. HaiRong, Z., Hao, P., Jingzhi, Shi., et al., Journal of Applied Polymer Science, 2011, 123 (2), 850-856. 2. Hu, Y. L., Feng, S. H., Bassi, A., et al., Energy Conversion and Management, 2018, 171, 618-625. 3. Mateus, M. M., Guerreiro, D., Ferreira, O., et al., Cellulose, 2017b, 24, 659-668.

110

Natural product chemistry PC31

ith dr aw n

Effect of gamma irradiation on physicochemical properties and antifunctional activity of essential oils of chilca (Baccharis latifolia) and muĂąa (Minthostachys mollis)

111

Pharmacokinetics and drug metabolism PC32

g-Cyclodextrin inclusion of efavirenz and its effect on aqueous solubility Karyna Lysenko,a Filipe A. Almeida Paz,b Susana S. Bragaa a

LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. b CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal.

Email: karynalysenko@ua.pt

Efavirenz (EFV) is an antiretroviral used to treat human immunodeficiency virus type 1 (HIV-1).1 However, in aqueous solution, the drug is poorly soluble and, consequently, it is deficiently absorbed by the gastrointestinal system.2 The main purpose of this study is to increase the aqueous solubility of EFV by inclusion into g-cyclodextrin (g-CD), testing different inclusion procedures and stoichiometries. Freeze-drying was the most successful method. The products were characterized in the solid state by Fourier-transform infrared spectroscopy, thermogravimetry, and X-ray powder diffraction. Furthermore, the preferential stoichiometry of the g-CD / EFV association in solution was determined by 1H nuclear magnetic resonance spectroscopy. The dissolution profile of EFV in PBS buffer, both from its pure form and the complexes with g-CD, was monitored by UV-Vis spectroscopy. Results show an unexpected preferred 2:1 stoichiometry (EFV:g-CD), and an evidence of increased dissolution of EFV from the inclusion complexes (Figure 1).

Figure 1: Dissolution of free EFV and its g-CD inclusion complexes with two different stoichiometries ,1:1 and 1:2 (g-CD:EFV). Acknowledgements: We acknowledge Fundação para a Ciência e a Tecnologia (FCT, Portugal), European Union, QREN, European Fund for Regional Development (FEDER), whenever applicable through the programme COMPETE, for general funding to the QOPNA research unit (project PEst C-QUI/UI0062/2019; FCOMP-01-0124-FEDER-037296) and the LAQV-REQUIMTE (UIDB/50006/2020), to CICECO (project UID/CTM/50011/2019) and to the Portuguese NMR network. References: 1. Maurin, M.B., Rowe, S.M., Blom, K.F., & Pierce, M.E. (2002). Kinetics and Mechanism of Hydrolysis of Efavirenz. Pharmaceutical Research, 19, 517-521. 2. Sathigari, S., Chadha, G., Lee, Y. H., Wright, N., Parsons, D. L., Rangari, V. K., Fasina, O. Babu, R. J. (2009). Physicochemical characterization of efavirenz-cyclodextrin inclusion complexes. AAPS PharmSciTech, 10(1), 81–87.

112

Pharmacokinetics and drug metabolism PC33

Montelukast metabolism: new insights into neurotoxicity Cátia F. Marques,a,b, Gonçalo C. Justino,a Catarina Gomes,b Francisco Ambrósio,b M. Matilde Marquesa a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal. bCoimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal

Email: catiafmarques@tecnico.ulisboa.pt Montelukast (MTK) is a cysteine leukotriene receptor 1 inhibitor currently used in asthma management. Although recently repurposed for other therapeutic applications, namely as chemopreventive and adjuvant in cancer therapy, as preventive agent in cardiovascular events and as anti-neuroinflammatory agent with potential application in neurodegenerative disorders, MTK has been associated with some adverse drug reactions (ADRs), namely neuropsychiatric effects.1-3 MTK metabolism is poorly understood and the mechanisms underlying ADRs remain unknown. Only 5 phase 1 and two phase 2 MTK metabolites have been identified and no association between metabolites and ADRs has been established.4 With the unexplained neurotoxicity of MTK and a potential repurposing of this drug as antineuroinflammatory agent in mind, our initial goal was to evaluate the in vitro and in vivo metabolism of MTK. MTK incubations with human and mouse subcellular fractions from different organs (brain, lung and liver) were performed, as well as with purified metabolic enzymes. MTK was also administered to C57BL/6J mice and their biofluids, faeces and selected organs were collected for analysis. Analyses were performed by ultraperformance liquid chromatography coupled to high-resolution electrospray ionization tandem mass spectrometry (UPLC-ESI-HRMS/MS). In addition to the known MTK metabolites, we identified novel phase I metabolites that resulted from hydroxylation, S-oxidation, N-oxidation and oxidative dealkylation, by analysis of their fragmentation pathways. In the presence of the adequate co-factors, we also identified new MTK-derived phase II metabolites, including glucuronide, glutathione, and cysteine conjugates. A new brain-specific decarboxylation metabolite was also observed. Preliminary results from in vivo studies support MTK excretion mainly in the bile. Hydroxylation products and glucuronide conjugates are the most abundant metabolites in vivo. Glutathione and cysteine adducts were found in different tissues, especially in brain tissue, supporting the hypothesis of neurotoxicity caused by MTK metabolites. Further work aims to determine possible MTK implications in the mechanisms of biological thiols, as well as the possible pharmacological activity of MTK adducts and MTK brain metabolites. Acknowledgements: This work was funded by Fundação para a Ciência e a Tecnologia (FCT; Portugal) through projects UID/QUI/00100/2019, UID/QUI/00100/2020, UID/NEU/04539/2019), COMPETE-FEDER (POCI-01-0145-FEDER-007440), Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER000008:BrainHealth 2020), and PTDC/QUI-QAN/32242/2017. We also acknowledge the financial support from FCT and Portugal 2020 to the RNEM (LISBOA-01–0145-FEDER-402–022125) IST Node (MS facility). CFM is an FCT PhD grantee (PD/BD/143128/2019).

References: 1. J. Marschallinger, I. Schäffner, B. Klein, R. Gelfert, F. J. Rivera, S. Illes, et al., Nat Commun. 2015, 6, 8466. 2. M. J. Tsai, P. H. Wu, C. C: Sheu, Y.-L.Hsu, W. A. Chang, J. Y. Hung, et al., Sci Rep. 2016, 6, 23979. 3. E. Ingelsson, L. Yin, M. Bäck.,J Allergy Clin Immunol. 2012, 129, 702. 4. J. de Oliveira Cardoso, R. V. Oliveira, J. B. L. Lu, Z. Desta, Drug Metab Dispos. 2015, 43, 1905.

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Pharmacokinetics and drug metabolism PC34

Immobilization of drug metabolizing enzymes in a nickel oxide foam: physico-chemical and enzymatic characterization Pedro C. Rosado,a Mafalda Macatrão,a Cátia F. Marques,a Ricardo Meyrelles,a Pedro F. Pinheiro,a Marta C. Justino,b,c Marta A. Alves,a Gonçalo C. Justino,a Ana Paula Ribeiro,a Karina Shimizua a Centro de Química Estrutural, Instituto Superior Técnico, University of Lisbon, 1049-001 Lisboa. b Escola Superior de Tecnologia do Barreiro, Instituto Politécnico de Setúbal, 2839-001 Lavradio. c Centro Interdisciplinar de Ciências Químicas e Biológicas, Instituto Politécnico de Setúbal, 2839-001 Lavradio.

Email: pedrocrosado@tecnico.ulisboa.pt

Assessing drug safety is crucial in the design of effective drugs. A significant number of current and under development drugs present toxic side effects. Most of these are due to bioactivation events during the normal cellular detoxification processes, where reactive electrophiles can be produced. These processes often result in drug ineffectiveness and toxicity, leading to market withdrawal. As such, the pre-clinical study of the potential metabolic pathways of these compounds is fundamental for toxicity evaluation. An effective method to accomplish this screening is by using purified enzymes1-3. To develop a cost-effective strategy, we have successfully subcloned, expressed and purified recombinant His-tagged sulfotransferase 1B1 isoform, into toxicity-resistant expression competent E. coli hosts. The purified functional enzymes were subsequently immobilized in nickel oxide foam supports. The enzyme-foam systems were characterized by SEM, ATR, XRD and BET, and specific binding of the His tails to the support was confirmed. DFT calculation on model systems predicted the favoured conformation of the His tails. The metabolizing capacity of these systems was evaluated using model substrates. The presence of the expected drug metabolites was confirmed by ultra-performance liquid chromatography coupled with high-resolution mass spectrometry, whereas the global enzymatic properties were maintained unaltered, as confirmed by the kinetic parameters. The catalytic activity and substrate specificity of the enzyme, as well as the regioselectivity of metabolite formation, was maintained upon immobilization. Enzymatic activity loss during the first six successive assays was ca. 30%. In particular, the metabolic profiles obtained with this system mimic the bioactivation events observed during the detoxification of antiretrovirals that are associated with severe adverse side effects. These results indicate that His-tagged protein immobilization on nickel oxide foams results in a cost-effective combination for enzymatic immobilization that can be successfully used to study drug metabolism in vitro, supporting the use of novel and profitable materials for the design of simple and accurate in vitro models, contributing to safer therapeutic approaches. Co-immobilization of different human metabolizing enzymes is currently under study, aiming at the simultaneous use of different proteins to generate a set of drug metabolic pathways, allowing for in vitro pathway mimicking. Acknowledgements: This work was supported by research projects SAICTPAC/0019/2015, PTDC/QUIQAN/32242/2017, PTDC/QUIQFI/29527/2017, and UID/QUI/00100/2019 and UID/QUI/00100/2020, funded by national funds through FCT and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. References: 1. Meyer UA. Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm. 1996;24(5):449-459. 2. Gómez-Lechón MJ, Tolosa L, Donato MT. Metabolic activation and drug-induced liver injury: In vitro approaches for the safety risk assessment of new drugs. J Appl Toxicol. 2016;36(6):752-768. 3. Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, McManus ME. Human sulfotransferases and their role in chemical metabolism. Toxicol Sci. 2006;90(1):5-22.

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Physical organic chemistry PC35

Aggregation-induced emission enhancement: principles, illustrations and applications Samuel Guieu LAQV-Requimte and CICECO Aveiro-Institute of Materials, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal, Email: sguieu@ua.pt

Most organic dyes are only luminescent in dilute solutions, and see their emission intensity dramatically quanched as soon as they interact with each other. But some fluorophores present the opposite behavior: they are weakly emissive in dilute solution, and their emission intensity increases when they form aggregates or are in the solid state (Figure 1). This behavior is known as aggregation-induced emission enhancement (AIEE), and result from the rigidification of the fluorophore backbone upon aggregation, which in turn blocks internal conversion and forces the chromophore to emit. This phenomenon has application in the production of organic luminescent materials and molecular probes for biological imaging.1

Figure 1: Structure of fluorophores presenting Aggregation-Induced Emission Enhancement.

Here, the principles of AIEE will be presented, illustrated with different families of dyes that have been prepared in our laboratory. The application of one series of fluorophores in biological imaging, namely for the detection of protein aggregates in live cells, will also be described. Acknowledgements: Thanks are due to University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program, and the European Union (FEDER program) via the financial support to the QOPNA research project (FCT UID/QUI/00062/2019), to the LAQV-REQUIMTE (UIDB/50006/2020), to the IBiMED Research Unit (UID/BIM/04501/2013; UID/BIM/04501/2019), to CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/ 50011/2019, financed by national funds through the FCT/MCTES, to the Portuguese NMR Network, to the ThiMES project (POCI-01-0145-FEDER-016630) and to the PAGE project “Protein aggregation across the lifespan” (CENTRO-01-0145-FRDER-000003). Samuel Guieu is supported by national funds (OE), through FCT, I.P., in the scope of the framework contract foreseen in the numbers 4, 5, and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19. We also thank the LiM facility of iBiMED/UA, a member of the Portuguese Platform of BioImaging (PPBI; POCI-01-0145FEDER-022122). References: 1. R. Nunes da Silva, C.C. Costa, M. J. G Santos, M. Q. Alves; S. S. Braga, S. I. Vieira, J. Rocha, A. M. S. Silva, S.Guieu Chem. Asian J. 2019, 14, 859. S. Guieu, J. Rocha, A. M.S. Silva, Tetrahedron 2013, 69, 9329. P. A. A. M. Vaz, J. Rocha, A. M. S. Silva, S. Guieu, New J. Chem. 2016, 40, 8198. S. Guieu, Química 2018, 42, 97. S. Guieu, F. Cardona, J. Rocha, A. M. S. Silva, Chem. Eur. J. 2018, 24, 17262. P. A. A. M. Vaz, J. Rocha, A. M. S. Silva, S. Guieu, New J. Chem. 2018, 42, 18166.

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Physical organic chemistry PC36

Fluorescent ureido-dihomooxacalix[4]arene-based receptors for anions and organic ion-pair recognition Alexandre S. Miranda,a,b Paula M. Marcos,a,c José R. Ascenso,d Mário N. Berberan-Santosb a

CQE, Faculdade de Ciências da Universidade de Lisboa, Edifício C8, 1749-016 Lisboa, Portugal. b IBB, Instituto Superior Técnico, 1049-001 Lisboa, Portugal. c Faculdade de Farmácia da Universidade de Lisboa, 1649-003 Lisboa, Portugal. d CQE, Instituto Superior Técnico,1049-001 Lisboa, Portugal Email: pmmarcos@fc.ul.pt

Anion recognition by synthetic receptors continues to attract much attention, as anions play essential roles in numerous biological systems, as well as in many environmental and industrial processes.1 On the other side, ditopic receptors, molecules capable of simultaneously bind both anion and cation of a given ion pair, have also been obtained and present important applications as membrane transport agents, and in salt extraction and solubilisation.2 Calixarenes, a very versatile class of macrocyclic compounds, bearing urea or thiourea moieties in the macrocycle scaffolds have been widely used in the recognition of anions and organic ion-pairs.3 The NH groups provide strong and directional hydrogen bonds providing deeply preorganized receptors. Following our previous studies on binding properties of dihomooxacalix[4]arene urea derivatives,4,5 we have extended our research into the study of fluorescent chemosensors for anion and ion-pair recognition. This work reports the host-guest properties of two dihomooxacalix[4]arenes bearing naphthyl urea groups on the lower rim (1 and 2), towards several relevant anions and also n-alkylammonium chlorides. These studies were performed by proton NMR, UV-Vis absorption and steady-state fluorescence titrations.

Acknowledgements: We thank Fundação para a Ciência e a Tecnologia, Project ref. UID/QUI/00100/2019 and A. S. Miranda thanks a PhD Grant, ref. SFRH/BD/129323/2017. References: 1. P. A. Gale, E. N. W. Howe, X. Wu, Chem. 2016, 1, 351. 2. A. J. McConnell, P. D. Beer, Angew. Chem. Int. Ed. 2012, 51, 5052. 3. Calixarenes and Beyond, P. Neri, J. L. Sesseler, M. X. Wang, Eds., Springer International Publishing, Switzerland, 2016. 4. F. A. Teixeira, P. M. Marcos, J. R. Ascenso, G. Brancatelli, N. Hickey, S. Geremia, J. Org. Chem. 2017, 82, 11383. 5. A. S. Miranda, D. Serbetci, P. M. Marcos, J. R. Ascenso, M. N. Berberan-Santos, N. Hickey, S. Geremia, Front. Chem. 2019, 7, Article 758.

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Physical organic chemistry PC37

Carvedilol and loratadine in the supercooled and glassy states: a DSC and dielectric study Hermínio P. Diogo, Maria Teresa Viciosa, Joaquim J. Moura Ramos Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal. Email: hdiogo@tecnico.ulisboa.pt The low solubility of crystalline drugs results in a low bioavailabity on the physiological ground that normally reduces the therapeutic window. A possible route for overcoming this drawback consists in using the Active Pharmaceutical Ingredient (API) in the amorphous solid state instead of its crystalline counterpart as is frequently marketed. However, the higher Gibbs free energy of the amorphous phase (compared to the crystalline one) constitutes a thermodynamic driving force to crystallization that needs to be controlled. The characterization of the glass stability of amorphous pharmaceutical solids is a very active research topic both at the fundamental level and in pharmaceutical technology, namely in the area of processability and manufacturing1. Furthermore, polymorphism is often associated with complex molecular structures, as are those of many commonly used drugs. Its occurrence must be properly controlled as otherwise it may result in non-reproducibility in batch at the scale-up level. In the present work the thermal behavior of two glass-forming API´s (carvedilol and loratadine, Figure 1) was studied by DSC, which allowed evaluating the glass-forming ability and the glass stability. The activation energy of the structural relaxation, the dynamic fragility, and the heat capacity jump at the glass transition were determined for both drugs from the DSC results. The dielectric technique of Thermally Stimulated Depolarization Currents (TSDC)2 was used to monitor different aspects of molecular mobility of both compounds in the amorphous state. The glass transition temperature, the activation energy of the structural relaxation and the dynamic fragility were obtained by TSDC and compared with the DSC results. In addition, a relaxation above Tg was observed in the TSDC thermogram of carvedilol (that presents a more flexible molecular structure) and the nature of this relaxation was assessed also by Dielectric Relaxation Spectroscopy (DRS). Finally, a secondary mobility in carvedilol, in the temperature region below Tg, was detected and characterized by the two dielectric techniques.

H N

N OH O NH

CH3 O

CH3

Figure 1: Molecular structures of carvedilol (left) and loratadine (right). Acknowledgements: This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal (Project UID/QUI/00100/2019). References: 1. a) D. P. Elder, J. E. Patterson, R. Holm, J. Pharm. Pharmacology 2014, 67, 757. b) H. Grohganz, K. Lobmann; P. Priemel, K. T. Jensen, K. Graeser, C. Strachan, T. Rades, J. Drug Del. Sci. Tech. 2013, 23, 403. 2. H. P. Diogo, M. T. Viciosa, J. J. Moura Ramos, Thermochim Acta 2016, 623, 29.

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Quantitative structure-activity relationships PC38

Chromones: a promising building block for medicinal chemistry Carlos F. M. Silva, Diana C. G. A. Pinto, Artur M. S. Silva LAQV-REQUIMTE, University of Aveiro, 3810-193 Aveiro, Portugal Email: silva.c@ua.pt

The quest for safer drugs remains the focus of several medicinal chemistry programs, with many families of compounds emerging as promising scaffolds for the development of novel active principles. Throughout the years, more and more natural products presenting encouraging pharmacological properties have been identified, designed, and synthesized. Chromones (4H-chromen-4-ones) (Figure 1), a group of naturally occurring compounds ubiquitous in plants, and the chromone core has proven to be a privileged scaffold in medicinal chemistry, since numerous derivatives have already been described as potential agents against a wide range of disorders. Herein we provide an overview of the potential of chromones for medicinal chemistry, emphasizing their anti-inflammatory activity1, through the inhibition of cyclooxygenase, lipoxygenase, interleukin-5 and nitric oxide production, and their potential ability to act against cholinesterases (AChE and BuChE), β-secretase and Aβ aggregation2. Furthermore, we intend to thoroughly demonstrate structure-activity relationship studies of these biological properties, to provide a deeper insight of structural features that might improved each of these activities allowing the development of novel active compounds or even multi-target-directed ligands (MTDLs).

Figure 1: Chromones, a family of promising anti-inflammatory and anti-AD agents.

Acknowledgements: Thanks are due to the University of Aveiro and FCT/MCT for the financial support for the QOPNA research Unit (UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. Carlos F. M. Silva also thanks FCT for his PhD grant (PD/BD/135103/2017). References: 1. Silva CFM, Pinto DCGA, Silva AMS. Chromones: A Promising Ring System for New Anti-inflammatory Drugs. ChemMedChem. 2016;11(20):2252-2260. doi:10.1002/cmdc.201600359 2. Silva CFM, Pinto DCGA, Silva AMS. Chromones: privileged scaffolds for the production of multi-targetdirected-ligand agents for the treatment of Alzheimer’s disease. Expert Opin Drug Discov. 2018;13(12):11411151. doi:10.1080/17460441.2018.1543267.

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Novel biologically active compounds PC39

Dodecyl 4,6-dideoxy glycosides towards B. anthracis with low cytotoxicity Patrícia Caladoa,b, Catarina Diasa, Amélia P. Rautera,b a

Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal bDepartamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal Email: patriciacalado95@hotmail.com

Antimicrobial resistance has become a serious global threat. In particular, Bacillus anthracis is a Gram (+) bacterium that exists as spores or as vegetative cells and has developed resistance to the clinically used antibiotics. Besides being epidemic in developing countries, this bacterium spores have been used as bioterrorism agent.1 Our group has been focused on the search for new carbohydrate-based potential antibiotics active against B. anthracis. The most promising compound is an O-glycoside embodying a dodecyl chain in the anomeric position with α configuration while having a 4,6-dideoxygenation pattern. It was active against B. cereus, E. faecalis and three strains of B. anthracis (pathogenic, sterne and ovine), with MIC = 12.6μM, accounting for half of the MIC value measured with the control (chloramphenicol, MIC = 25μM). However, amongst the tested deoxy glycoside compounds, the synthesized C-glycosides showed the lower cytotoxicity on Caco-2 cells.2,3 Thus, the aim of this work was to explore an efficient synthetic route towards the dodecyl C-glycoside embodying the same glycone structure as that of the most active sample (Figure 1). Three different synthetic routes were explored, starting from either the naturally occurring D-glucose or its methyl glucoside. The first approach (A) started from D-glucose protected with a 4,6-O-benzylidene group while embodying benzyl groups in the remaining positions. However, regioselective opening of the benzylidene group with NIS revealed unsuccessful due to the reagent incompatibility with the ether protecting groups. In the second route (B), staring from methyl α -D-glucoside, positions 4 and 6 were also protected with benzylidene group while positions 2 and 3 were acetylated. Posterior complete reduction of the acetal protecting group, followed by iodination of both 4 and 6 posi tions and its dehalogenation, afforded an inseparable mixture (3:1 8/9) of the required 4,6-dideoxy glycoside (8) and a 4,6- cyclo4,6-dideoxy glycoside (9). It was adopted synthetic route C, where it was performed a regioselective opening of the benzylidene group with sodium cyanoborohydride and iodine, to afford an OH group in posi tion 4 and a benzyl group in position 6. A sequence of iodination/hydrogenation reactions afforded the deoxygenation in positions 4 and 6, originating compound 8. The acetolysis of the anomeric carbon and the allylation reaction were the key steps to afford the C-glycoside precursor. Finally, a metathesis reaction with a 2nd generation HoveydaGrubbs catalyst was performed, enabling the elongation of the alkyl chain. The hydrogenation of the alkyl chain double bond and the hydrolysis of the acetyl groups afforded the final compound 19 with 13% yield over 13 synthetic steps. Further biological assays will disclose the new compound’s effectiveness against B. anthracis and also its cytotoxicity for further lead developments.

Figure 1. Structure of the C-glycoside target molecule. Acknowledgements: The authors are grateful to Fundação para a Ciência e a Tecnologia for the financial support of Centro de Química Estrutural (UID/QUI/00100/2019) and of Centro de Química e Bioquímica (UID/Multi/00612/2019). This work was also supported by the project “Diagnostic and Drug Discovery Initiative for Alzheimer’s Diseases” (D3i4AD), FP7 – PEOPLE – 2013 - IAPP, GA 612347. References: 1. Kock, R., Haider, N., Mboera, L. E. & Zumla, A. A One-Health lens for anthrax. Lancet Planet. Heal. 3, e285–e286 (2019). 2. Dias, C. et al. Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes. Nat. Commun. 9, 4857 (2018).

3. Dias, C. et al. Assessing the Optimal Deoxygenation Pattern of Dodecyl Glycosides for Antimicrobial Activity Against Bacillus anthracis. European J. Org. Chem., 2224–2233 (2019

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Novel biologically active compounds PC40

Synthesis and characterization of a hybrid based on porphyringraphene quantum dots: a preliminary assessment towards breast cancer cells Cristina J. Dias,a Carla I. M. Santos,a,b Gil Gonçalves,c Fátima L. Monteiro,d Maria G. P. M. S. Neves,a Luisa A. Helguero,d Maria A. F. Faustino,a M. Ángeles Herranz,e Nazario Martin,e José G. Martinho,b Ermelinda Maçôasb a

LAQV-Requimte and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. b CQFM, Centro de Química-Física Molecular, IN-Institute of Nanosciences and Nanotechnology, CQE, Centro de Química Estrutural, Instituto Superior Técnico, 1049-001 Lisboa, Portugal. c TEMA-Nanotechnology Research Group, Mechanical Engineering Department, University of Aveiro, 3810-193 Aveiro, Portugal. d Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal. e Department of Organic Chemistry, Faculty of Chemistry, Universidad Complutense de Madrid, E-28040 Madrid, Spain

Email: cristina.jesus.dias@ua.pt

The unique chemical and physical properties of carbon nanomaterials have attracted the attention of the scientific community in the past few years.1 In particular, graphene quantum dots (GQDs) possess excellent optical properties, high photostability, aqueous solubility and biocompatibility, which allow their application in different fields such as catalysis, nanoelectronic devices, nanocomposite materials, energy devices, and in biomedical applications, namely in imaging, biosensing, drug delivery and photodynamic therapy (PDT).1,2 PDT has been outstanding in the treatment of several tumors and it involves the selective photosensitizers (PS) uptake by tumor cells, which upon light exposure in the presence of dioxygen will trigger the formation of locally reactive oxygen species leading to cell death.3 Thus, the distinctive properties of GQDs and the presence of carboxyl and hydroxyl groups on their surface provides the opportunity to explore them as anchoring units for covalent functionalization to photoactive molecules, such as PS used in PDT.2 The aim of this study was to prepare a biocompatible hybrid GQD-Porph A resulting from the covalently linkage of GQDs to Porph A bearing a 2-aminoethylamino chain (Scheme 1) and assessment of its internalization and cytotoxicity in the T47-D breast cancer cell line.

Scheme 1: Preparation of the hybrid by covalently linkage to Porph A.

Acknowledgements: Thanks are due to the University of Aveiro, Instituto Superior Técnico de Lisboa and FCT/MCT for the financial support for the QOPNA (FCT UID/QUI/00062/2019), LAQV-REQUIMTE (UIDB/50006/2020), Institute for Biomedicine – iBiMED (UID/BIM/04501/2019), CQE-IST (UID/CTM/50011/2019, PTDC/NAN-MAT/29317/2017, PTDC/QUI-QFI/29319/2017 and UID/NAN/50024/2019) and to project PREVINE (FCT-PTDC/ASP-PES/29576/2017) through national funds (OE) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and Internationalization-COMPETE 2020, within the PT2020 Partnership Agreement. Thanks are also due to the Portuguese NMR and Mass Networks. C. J. Dias also thanks FCT for her research grant (BI/UI51/8448/2018). C. I. M. Santos acknowledges the research contract (REF.IST-ID/95/2018) funded by national funds (OE), through FCT (Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19). F. L. Monteiro also acknowledges (SFRH/BD/117818/2016). Image acquisition was performed in the LiM facility of iBiMED, a node of PPBI (Portuguese Platform of BioImaging): POCI-01-0145-FEDER-022122. References: 1. X. Cui, S. Xu, X. Wang, C. Chen. Carbon 2018, 138, 436. 2. C. I. M. Santos et al. Carbon 2018, 135, 202. 3. H. Abrahamse, M. Hamblin. Biochem J. 2016, 473, 347.

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Novel biologically active compounds PC41

Functionalization of graphene oxide with porphyrins and terpyridine-like compounds via non-covalent interactions Ana R. Monteiro,a,b Tito Trindade,b Maria G. P. M. S. Nevesa a

LAQV-Requimte, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. b CICECO, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal

Email: anarita.rvcm@ua.pt

Porphyrins and terpyridines, due to their remarkable individual properties, have found applications in a wide variety of fields, namely in biological applications.1,2 In order to enhance their potential as antitumoral agents, these organic molecules have been used in the functionalization of twodimensional layered and biocompatible materials, namely graphene oxide (GO).3 The current work aims to explore the non-covalent functionalization of GO with porphyrins and terpyridines. The latter compounds should have positive charges and/or aromatic groups, in order to enhance the non-covalent interactions to the negatively-charged flat sheets of GO at physiological pH. The 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) was selected as a reference model, since its potential as an efficient cancer drug has been widely reported.1 Its zinc(II) derivative (ZnTMPyP ) has been studied to evaluate the role of the core metalation of porphyrins on the interactions to GO. The selection of 4’-p-tolyl-2,2’:6’,2’’-terpyridine (ttpy) allowed to study the interactions of individual terpyridine units to GO, since one of the future aims of this work is to synthesize porphyrins containing terpyridine units at their meso positions through the reaction between terpyridine aldehydes and pyrrole. In order to achieve the aforementioned aim, a primary step was explored towards a new synthetic route to develop the terpyridine aldehyde, 4’-(4formylphenyl)-2,2’:6’,2’’-terpyridine (CHOtpy). TMPyP was synthesized through a condensation reaction between pyrrole and 4-pyridinecarboxaldehyde and further cationized with iodomethane. The ZnTMPyP was obtained through the reaction with the respective metal salt. Ttpy was obtained through solventless aldol condensation between 2-acetylpyridine and p-tolualdehyde, in the presence of a catalytic amount of base. Then, the as-synthesized product was transferred to a suspension of ammonium acetate in glacial acetic acid, heated in reflux system, and precipitated upon addition of water. A similar approach was done to obtain CHOtpy through the reaction of 2acetylpyridine and 4-(diethoxymethyl)benzaldehyde. The hybrid materials were synthesized through successive titrations of porphyrin or terpyridine with GO. The characterization of the as-developed materials was followed by UV-Vis spectroscopy, fluorescence, Raman spectroscopy and electron microscopy. Alternative methods to promote the non-covalent functionalization were also explored. The as-developed hybrid materials will be further tested as potential drug loading and releasing systems of cancer drugs.

Scheme 1: Non-covalent hybrids between porphyrins and graphene oxide. Acknowledgements: The authors thank the University of Aveiro and FCT (Fundação para a Ciência e Tecnologia) for the financial support to the LAQV-Requimte research Unit (FCTUID/QUI/00062/2019) and CICECO-Aveiro Institute of Materials (Ref.UID/CTM/50011/2019), through national funds through the FCT/MCTES and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement. Ana R. Monteiro thanks the FCT for the PhD grant SFRH/BD/137356/2018. The authors thankfully acknowledge the Portuguese NMR Network. References: 1. A. Garcia-Sampedro, A. Tabero, I. Mahamed, P. Acedo, J Porphyr Phthalocya, 2019, 23, 11. 2. N. M. M. Moura, C. I. V. Ramos, I. Linhares, S. M. Santos, M. A. F. Faustino, A. Almeida, J. A. S. Cavaleiro, F. M. L. Amado, C. Lodeiro, M. G. P. M. S. Neves, RSC Adv, 2016, 6, 110674. 3. S. Su, J. Wang, R. Martínez-Zaguilán, J. Qiu, S. Wang, New J Chem, 2015, 39, 5743.

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Novel biologically active compounds PC42

Photodynamic therapy of prostate cancer using chlorin and isobacteriochlorin derivatives Mariana Q. Mesquita,a,b Maria G. P. M. S. Nevesa, Margarida Fardilhab, Maria A. F. Faustinoa a

LAQV-Requimte and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. bDepartment of Medical Sciences, Institute of Biomedicine – iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal Email: marianamesquita@ua.pt

Prostate cancer is the second most common cancer in men. Conventional options to treat this cancer can involve radical prostatectomy, transperineal brachytherapy, radiotherapy, and/or androgen-deprivation therapy. However, the majority of these treatments cause several side effects and have a significant impact in the quality of life of each patient.1,2,3 Consequently, this dilemma led to the development of focal therapy for localized prostate cancer, which aims to reduce the side effects seen with radical therapy, while maintaining oncological control.1 Photodynamic therapy (PDT) is a clinically approved therapy that can be used for early stage diseases.2 In particular, prostate cancer emerges as a promising target for focal PDT.4 This therapy involves the administration of a photosensitizer (PS) that in the presence of oxygen is selectively activated by light to cause cell death through the production of reactive oxygen species.5 Porphyrins are the most extensively studied PSs used in PDT due to their absorption in the visible range, long-lived triplet excited state, and effective phototoxicity towards cancer cells. Additionally, several analogues such as chlorins and isobacteriochlorins, which can be prepared from porphyrins, can also be promising PS.6 As a matter of fact, chlorins and isobacteriochlorins possess greater absorption in the red region of the visible spectrum than porphyrins, allowing them to cause deeper tissue photodamage.6 In this study, we describe the synthetic strategy to obtain chlorin and isobacteriochlorin derivatives using 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin as template and we discuss their spectroscopic and photophysical properties. A preliminary evaluation of their phototoxicity against the prostate cancer cell line PC-3 will be also be presented. Acknowledgements: Thanks are due to the University of Aveiro and FCT/MCT for the financial support of the QOPNA research Unit (FCT UID/QUI/00062/2019), the LAQV-REQUIMTE (UIDB/50006/2020) and Institute for Biomedicine – iBiMED (UID/BIM/04501/2013 and POCI-01-0145-FEDER-007628) through national funds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. MM thanks FCT for her doctoral grant (SFRH/BD/112517/2015).

References: 1. L. Wang, H. Yang, B. Li, Prostate Int. 2019, 7, 83. 2. T. Gheewala, T. Skwor, G. Munirathinam, Oncotarget. 2017, 8, 30524. 3. F. Z. Leandro, J. Martins, A. M. Fontes, A. C. Tedesco. Colloids Surf B Biointerfaces. 2017, 154, 341. 4. A. Kawczyk-Krupka, K Wawrzyniec, S. K. Musiol, M, Potempa, A. M. Bugaj, A. Sieroń. Photodiagnosis Photodyn. Ther. 2015, 12, 567. 5. M. Q. Mesquita, C. J. Dias, S. Gamelas, M. Fardilha, M. G. P. M. S. Neves, M. A. F. Faustino, An. Acad. Bras. Ciênc. 2018, 90, 1101. 6. S. Singh, A. Aggarwal, N. V. S. D. K. Bhupathiraju, G. Arianna, K. Tiwari, C. M. Drain. Chem. Rev. 2015, 115, 10261.

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Novel biologically active compounds PC43

Probing the medicinal properties of 3(5)-(2-hydroxyphenyl)-5(3)styryl-1H-pyrazoles and their ruthenium complexes Susana S. Braga, Nádia E. Santos, Susana M. Cardoso, Vera L. M. Silva LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. Email: sbraga@ua.pt

The 3,5-disubstituted pyrazole core is a pharmacophore present in a variety of compounds with medicinal activity, from leishmanicidals1 to anti-inflammatory agents.2 In this work, we report the antioxidant activity of 3(5)-(2-hydroxyphenyl)-5(3)- (4-R-styryl)-1Hpyrazoles (phpz), with R = H or Cl. The activity is determined by the ABTS assay and compared to that of two analogues that are methylated at the H1 of the pyrazole and the OH-2 position of the phenol; these protected pyrazoles aim at a better understanding of the contribution of the functional groups towards the antioxidant activity. The pyrazoles were further complexed with a face-capped ruthenium precursor to obtain [Ru(II)([9]aneS3)(phpzR)(DMSO)Cl]Cl complexes, where [9]aneS3 is trithiacyclononane and R represents H or Cl (Scheme 1). Another complex of this family, bearing R = OCH3, is already reported to exert potential antiproliferative activities toward prostate cancer (PC-3) and breast cancer (MDA-MB-231) cell lines.2 Based on that, it is expected that the two new complexes may also be good candidates to antitumoural drugs. In this context, DNA intercalating properties of the complexes were evaluated by measuring their ability to shift the DNA mean denaturation temperature (Tm). Both complexes showed intercalion capacity with DNA, having ΔTm values of +20 ºC and +17 ºC (for Ru-phpzH and Ru-phpzCl, respectively). + S S

phpz-R, ethanol reflux

S Ru Cl

DMSO

Ru DMSO

R = H or Cl

Scheme 1: Preparation of the ruthenium trithiacyclononane complexes of 3-(2-hydroxyphenyl)-5styrylpyrazole.

Acknowledgements: We thank Fundação para a Ciência e a Tecnologia (FCT, Portugal), European Union, QREN and the European Fund for Regional Development (FEDER), through the programme COMPETE, for general funding (project PEst C-QUI/UI0062/2019; FCOMP-01-0124-FEDER-037296) and to the Portuguese NMR network.. References: 1. C. E. Mowbray, S. Braillard, W. Speed, P. A. Glossop, G. A. Whitlock, K. R. Gibson, J. E. J. Mills, A. D. Brown, J. M. F. Gardner, Y. Cao, W. Hua, G. L. Morgans, P.-B. Feijens, A. Matheeussen, L. J. Maes, J Med Chem 2015, 58, 9615. 2. J. Marques, V.L.M. Silva, A.M.S. Silva, M.P.M. Marques, S.S. Braga, Complex Met. 2014, 1, 7.

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Novel biologically active compounds PC44

G-quadruplex intercalative interaction of a small doubly charged ligand Catarina I. V. Ramos, Vítor A. S. Almodôvar, Augusto C. Tomé, M. Graça P. M. S. Neves LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal Email: c.ramos@ua.pt

G-quadruplexes (GQ) are DNA secondary structures that are reported to be found in several genome regions of biological significance, especially in the telomeres,1 which are non-coding regions at the ends of the chromosomes. Telomeres act as chromosome “sealants” stabilizing the linear strands and preventing their damage. In normal somatic cells, telomeres are shortened in the process of DNA replication and eventually become too short to protect the chromosome, leading to cell senescence and death. Many cancer cells can counteract this shortening by increasing the level of activity of telomerase, a reverse transcriptase enzyme, which allows continual cell division without telomere shortening. Telomerase is expressed in a range of cancer cells2 and stabilization of the GQ structures in the terminal region of the telomeres has been reported to inhibit telomerase activity. Consequently, GQ have emerged as a new class of novel molecular targets for the design of anticancer drugs.3 Several studies have shown that cationic tetrapyrrolic derivatives, such as phthalocyanines and porphyrins, in particular the multicharged 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) exhibits high affinity to GQ-DNA and thus it is a potential telomerase inhibitor. However, it is also recognized that this cationic ligand has poor selectivity for GQ over duplex DNA structures.4 We report here the ability of a small doubly charged ligand to form adducts with DNA. By using UVVis titrations, the stability of ligand-DNA quadruplex and duplex conformations was evaluated, and the results obtained showed a high affinity and selectivity of this molecule for G-quadruplex conformations when compared with duplex structures such as calf thymus and ds26. The analysis of the hypochromic and bathochromic effects in the ligand UV-Vis spectra due to the presence of the DNA allowed to predict that the interaction of the ligand in the G-quadruplex structure occurs by intercalation instead of end-stacking in the G-quadruplex structure reported for TMPyP and phthalocyanines.4

Figure 1: G-quadruplex-ligand adduct formation and telomerase inhibition. Acknowledgements: Thanks are due to the University of Aveiro and FCT/MCT for the financial support for the QOPNA research Unit (FCT UID/QUI/00062/2019), the LAQV-REQUIMTE (UIDB/50006/2020) and to project PTDC/QEQQOR/6160/2014 through national funds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. C.I.V. Ramos thanks University of Aveiro for her research contract (REF.047-88-ARH/2018). V.A.S. Almodôvar thanks FCT for his doctoral grant (SFRH/BD/135598/2018). References: 1. a) G. W. Collie, G. N. Parkinson Chem Soc Rev, 2011,40, 5867; b) J. Nandakumar, T.R. Cech. Nat. Rev. Mol. Cell Biol. 2013, 14, 69. 2. a) A.L. Moye, K.C. Porter et al. Nat. Commun. 2015, 6, 1; b) Z. Schrank, N. Khan et al., Molecules 2018, 9, 2267. 3. a) L.Oganesian, T. M. Bryan et al. BioEssay 2007, 29, 155; b) Q. Wang, J.Q. Liu, et al. Nucleic Acids Res. 2011, 39, 6229; c) J. Bidzinska, G. Cimino-Reale ,et al. Molecules 2013, 18, 12368. 4. a) C. Romera; O. Bombarde, et al. Biochimie 2011, 93, 1310; b) L.N.Zhu, B. Wu et al.; Nucleic Acids Res. 2013, 41, 4324; c) S. Zhang, Y. Wu et al. Chem Med Chem 2014, 9,899 ; d) A.R. Monteiro, C. I. V. Ramos; et al. ACS Omega 2018, 3, 11184; e) C. I. V. Ramos, S. P. Almeida et al. Molecules, 2019, 24, 733.

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Novel biologically active compounds PC45

Stable boron heterocycles as stimuli-responsive linkers for the preparation of targeted bioconjugates João P. M. António,a Hélio Faustino,a Luis F. Veiros,b Pedro M. P. Góisa a Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. b Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av.Rovisco Pais 1, 1049-001 Lisboa, Portugal

Email: jantonio@ff.ulisboa.pt

In recent years targeting drug conjugates emerged as a powerful class of anticancer therapeutics that can lessen the systemic toxicity of traditional chemotherapy, by combining the lethality of potent cytotoxic drugs with the targeting ability of biomolecules. The linker that connects both targeting and cytotoxic components is determinant to improve the conjugate’s therapeutic index, as it is responsible for maintaining the conjugate integrity in circulation and for triggering the drug release only upon reaching the target. To do so, the linker must be responsive to a particular stimuli, specific from tumor environment. Due to an accelerated metabolism, reactive oxygen species (ROS) are generally overexpressed in tumor cells and have been widely explored to design responsive drug delivery systems. Boronic acids, for example, have been widely used as a ROS-responsive handle but show promiscuous reactivity with endogenous molecules and are unsuitable to be used without supramolecular protection. We hereby present diazaborines (DABs) as a stable and ROS-responsive scaffold that can be used as a linker in tumor-targeting bioconjugates. A small library of diazaborines was easily prepared from the reaction of hydrazines with ortho-carbonyl benzene boronic acids. The formation kinetics and their correspondent stability were assessed and the optimal scaffold, generated from o-formyl benzene boronic acid and alkylic hydrazines, was selected for further evaluation. The selected core was stable for up to 14 days at pH 4.5, 7.0 and 9.0 and showed no visible degradation in plasma up to 6 days. Nevertheless, in the presence of 100 equivalents of hydrogen peroxide (selected model for ROS), the DAB was swiftly oxidized (t1/2 = 15 minutes) to the correspondent phenol, followed by spontaneous hydrolysis of the hydrazone to release the hydrazine payload (Scheme 1A). The oxidation kinetics were evaluated at different concentrations of DAB and hydrogen peroxide, different pH and in the presence of interfering molecules (e.g. glutathione). A detailed DFT study was also performed to elucidate the oxidation mechanism and support the experimental observations. To demonstrate the utility of this new technology, a model targeting peptide was modified with a cytotoxic drug through a selfimmolative DAB linker. The stability of the conjugate was assessed (stable at different pH and plasma) and selective oxidation was observed exclusively in the presence of hydrogen peroxide, promoting the release of the cytotoxic payload (Scheme 1B).

Acknowledgements: We thank FCT for the financial support (iMed.ULisboa grant UID/DTP/ 04138/2013, PTDC/QEQ-QOR/1434/2014, MedChemTrain grant PD/BD/128239/2016)

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Novel biologically active compounds PC46

Structure-activity relationships of cationic imidazolyl photosensitizers for sub-micromolar inactivation of bacteria Rafael T. Arosoa, Carolina S. Vinagreiroa, Janusz M. Dabrowskib, Fabio Schaberlea Gabriela Jorge da Silvad, Vanderlei S. Bagnatoc, Luis G. Arnauta, Mario J. F. Calvetea, Mariette M. Pereiraa a

CQC, Department of Chemistry, University of Coimbra, Coimbra, Portugal; bFaculty of Chemistry,Jagiellonian University, Krakow, Poland; c São Carlos Institute of Physics, University of São Paulo, Brazil; d Faculty of Pharmacy and Center for Neurosciences and Cell Biology, University of Coimbra, Portugal

Email: rafael.aroso@student.uc.pt Over the last few decades, no major discoveries have been made regarding new, ground-breaking, antibiotics, which could resolve or, at least, delay the worrying onset of infections by multi-resistant gram-negative bacteria infections.1 This has trigged an increasing interest in the search for different antimicrobial action mechanisms for which low to no resistance has yet been observed. To address this issue, photodynamic inactivation (PDI)2 is a promising light-dependent alternative therapy for the treatment of localized infections (Scheme 1). Herein we present our developments on the synthesis of two families of cationic imidazolyl-based tetrapyrrolic macrocycles (porphyrins and phthalocyanines). Aiming towards comprehensive structural-activity relationships, various derivatives were synthesized. Their efficacy towards inactivation of gram-positive, gramnegative and fungi was tested, as well as their phototoxicity towards mammalian cells. Confocal microscopy studies were also performed to give insights on the cellular localization of the photosensitizers. Regarding the phthalocyanine family, their antimicrobial activity in combination with white light (10 J/cm2) yielded remarkable differences among all tested compounds. Metal and alkyl chain are key issues to selectively kill gram-negative species (E. coli, P. aeruginosa) and C. albicans, in nanomolar concentrations (100 nM), while leaving mammalian cells almost intact. These results makes them promising leads for treatment of localized infections.3 With respect to the development of a new cationic imidazolyl porphyrin family, their antimicrobial activity were tested in a panel of planktonic wild-type and multidrug-resistant strains (Staphylococcus aureus, E. coli, P. aeruginosa), in addition to S. aureus biofilms. Total inactivation was found for concentrations as low as 100 nM (wild-type) and 1 µM (multidrug-resistant) in planktonic bacteria, with irradiation at 415 nm (LED, 1.4 J/cm2). Moreover, in the inactivation of S. aureus biofilms, a notable effect of size and number of charges was observed, achieving a total destruction of the biofilm (7log units)4 with irradiation at 400-650 nm (5 J/cm2)and with just a 5.2 nM concentration of the smaller photosensitizer.2 In this communication, we will discuss the synthesis and effects of the amphiphilicity, size of the cationizing alkylic chains, number and distribution of positive charges and central coordinating metal on their biological activity. Overall, we found unique and insightful structure-activity relationships for these families of cationic imidazolyl tetrapyrrolic macrocycles, which may contribute to the rational design of photosensitizers for use in photodynamic inactivation of microorganisms.

Scheme 1: Schematic representation of PDI using the aforementioned families of cationic imidazolyl photosensitizers. Acknowledgements: Fundação para a Ciência e a Tecnologia (FCT) for projects UID/QUI/00313/2019 and POCI-01-0145FEDER-027996. Rafael T. Aroso thanks FCT for scholarship grant PD/BD/143123/2019. Carolina S. Vinagreiro thanks FCT for PhD grant PD/BD/128317/2017. References: 1. M. S. Butler, M. A. T. Blaskovich, M. A. Cooper, J. Antibiot. 2017, 70, 3. 2. E. Alves, L. Costa, C. M.B. Carvalho, J.P.C. Tomé, M. A. Faustino, M. G. P. M. S. Neves, A. C. Tomé, J. A. S. Cavaleiro, A. Cunha, A. Almeida, BMC Microbiology 2009, 9, 70 3. R. T. Aroso, M. J.F. Calvete, B. Pucelik, G. Dubin, L. G. Arnaut, M. M. Pereira, J. M. Dabrowski, Eur. J. Med. Chem. 2019, 184, 111740 4. Small cationic ortho-5,15-di-heteroaryl-porphyrins derivatives and their applications in photoinactivation of microorganisms submitted on 14/06/2019 nº 20191000032263, Portugal

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Novel biologically active compounds PC47

Xanthone derivatives as inhibitors of P-glycoprotein and of tumor cell growth: synthesis and biological evaluation Diana I. S. P. Resende,a Bárbara A. S. Cruz,b Diana Ribeiro,c Patrícia P. M. A Silva,c Hassan Bousbaa,a,c Renata Silva,b Fernando Remião,b Madalena M. M. Pinto,a,d Emília Sousaa,d,* a

Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), 4450-208 Matosinhos, Portugal. b REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. c CESPU, Instituto de Investigacão e Formacão Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal. d Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.

Email: esousa@ff.up.pt

P-glycoprotein (P-gp), an efflux bomb that belongs to the ABC transporters superfamily, is widely distributed through the body and is responsible for limiting the cellular uptake and the distribution of xenobiotics, including drugs.1 Multidrug resistance (MDR) is one of the main reasons for the inefficiency of cancer chemotherapy and, therefore, P-gp modulation (particularly inhibition) can be an important therapeutic strategy.2 Knowing that xanthones have demonstrated to be drug candidates as antitumor agents3 and also showed ability to interact with P-gp,4 it is important to explore the dual activity of new xanthonic derivatives as P-gp and tumor cell growth inhibitors. In this study, four xanthone derivatives bearing different substituents (Figure 1) were synthesized and their cytotoxicity was tested against three human cancer cell lines (A375-C5, MCF7, and NCI-H460) by the SRB assay with promising results. Evaluation of the potential effect of these xanthonic derivatives in P-gp expression and/or activity, in Caco-2 cells, revealed that two of them acted as P-gp inhibitors, resulting in a significant increase in the cytotoxicity of two P-gp substrates. Indeed, the evaluation of their ability to change the cytotoxicity of quinidine and daunorubicin (DAU), the two P-gp substrates tested, demonstrated that one of the derivatives, due to the highest inhibitory potency demonstrated, represents a putative P-gp inhibitor that could be used in cases of MDR development, promoting the accumulation of drugs that are P-gp substrates at the target organs/tissues, and increasing their therapeutic efficiency.

Figure 1: Xanthone derivatives 1-4. Acknowledgements: Support for this work was provided by the Strategic Funding UID/Multi/04423/2019 and under the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds. References: 1. Zhou, S.-F. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition, Xenobiotica 2008, 38, 802. 2. Vilas-Boas V., Carmo H., Dinis-Oliveira R.J., Carvalho F., de Lourdes Bastos M., Remiao F. Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy. Pharmacol. Ther. 2015, 149, 1. 3. Barbosa, J., Lima, R. T., Sousa, D., Gomes, A. S., Palmeira, A., Seca, H., Choosang, K., Pakkong, P., Bousbaa, H., Pinto, M. M., Sousa, E., Vasconcelos, M. H., Pedro, M. Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis. Molecules 2016, 21, 81. 4. Martins, E., Silva, V., Lemos, A., Palmeira, A., Puthongking, P., Sousa, E., Rocha-Pereira, C., Ghanem, C. I., Carmo, H., Remião, F., Silva, R. Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies. Molecules 2019, 24, 707.

127

Novel biologically active compounds PC48

Synthesis of 2-aroylfuro[3,2-c]quinolines from quinolone-based chalcones and evaluation of their antioxidant and anticholinesterase activities João P. S. Ferreiraa, Susana M. Cardosoa, Filipe A. Almeida Pazb, Artur M. S. Silvaa, Vera L. M. Silvaa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. bCICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. Email: joaof@ua.pt

Among quinoline derivatives, furoquinolines have been the focus of attention of scientists due to their natural occurrence in several alkaloids. Compounds of this class have been isolated mainly from plants of Rutaceae family and can be found either in linear (furo[2,3-b]quinolines) and angular (furo[3,2c]quinolines) forms. These types of compounds are recognized by their important role in medicine, namely as antifungal, antiviral, antimicrobial, antitumoral and anticholinesterasic agents.1 Given the biological importance of these compounds, several methods have been developed for their synthesis. Yet, most of them provided furo[2,3-b]quinolines and only a few references focused the synthesis of furo[3,2-c]quinolines.2,3 In fact, so far, only one paper described the two-step synthesis of furo[3,2-c]quinolines from quinoline-2(1H)-one-based chalcones.4 Inspired by these previous findings and following our interest in the synthesis and biological evaluation of furoquinolines,5 we will present our results on the synthesis of novel angular furoquinolines, more specifically 2-aroylfuro[3,2-c]quinolines 2 starting from (E)-3-(3-aryl-3-oxoprop-1en-1-yl)quinolin-4(1H)-ones 1. When starting from compound 1e an unexpected product (compound 3) was obtained and its structure was identified (Figure 1). The potential of compounds 2a-e and 3 to inhibit oxidative stress and acetylcholinesterase activity (i.e two key events in Alzheimer’s disease)6 was evaluated in chemical models, with the first being assessed through the ability to scavenge the free radicals 2,2-azinobis-(3-ethylbenzothiazoline-6sulfonic acid) and nitric oxide (ABTS+• and NO•, respectively). Albeit these compounds were not effective against these radical species, compounds 2a and 2c could be promising templates for the development of novel AChE inhibitors.

Figure 1. Synthesis of 2-aroylfuro[3,2-c]quinolines 2a-e from quinolone-based chalcones 1a-e in one step. Acknowledgements: We thank to University of Aveiro and FCT/MEC for the financial support to the QOPNA research project (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020), financed by national funds and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement and to the Portuguese NMR network. Vera L. M. Silva thanks funding from national funds through the FCT-I.P., in the framework of the execution of the program contract provided in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/2016 of 29 August, as amended by Law no. 57/2017 of 19 July. References: 1. A. Adamska-Szewczyk, K. Glowniak, T. Baj, Curr. Issues Pharm. Med. Sci. 2016, 29, 33-38. 2. Y.-L. Chen, I.-L. Chen, T.-C. Wang, C.-H. Han, C.-C. Tzeng, Eur. J. Med. Chem. 2005, 40, 928-934. 3. A. Fayol, J. Zhu, Angew. Chem. 2002, 114, 3785-3787. 4. D. K. Kumar, S. P. Rajendran, Synth. Commun., 2012, 42, 2290-2298. 5. V. L. M. Silva, A. M. S. Silva, Tetrahedron, 2014, 70, 5310-5320. 6. J.B. Melo, P. Agostinho, C.R. Oliveira, Neurosci. Res. 2003, 45, 117-127.

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Novel biologically active compounds PC49

Photodynamic therapy using thioglycerol porphyrin and phthalocyanine derivatives Joana M. D. Calmeiro,a Andreia Melo,b Rosa Fernandes,b,c João P. C. Tomé,d Leandro M. O. Lourençoa a

LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. b iCBR, Faculty of Medicine, University of Coimbra, Portugal. c CNC.IBILI Consortium, University of Coimbra, Portugal. d CQE and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.

Email: jcalmeiro@ua.pt

Photodynamic Therapy (PDT) has been successfully employed in the treatment of various types of solid tumors, since its approval.1 This therapy uses three elements: visible light, molecular oxygen and a photosensitizer (PS, photoactive drug). When these elements are combined, the light activates the PS, which can transfer energy to the molecular oxygen for the generation of reactive oxygen (ROS) species. These cytotoxic oxygen species can induce cell death pathways and consequently tumor tissue destruction.2 For this reason, the search for more powerful and selective PSs is still a very hot research area on porphyrins (Pors) and phthalocyanines (Pcs). These two types of PSs have been showing unique photochemical and photophysical properties for PDT.3 In this context, it will be reported and discussed the synthesis and characterization of a tetra-thioglycerol free-base porphyrin 1 and a octa-thioglycerol zinc(II) phthalocyanine 2 (Figure 1) on bladder cancer PDT will be also analysed.

Figure 1: Structure of porphyrin (left) and phthalocyanine (right) derivatives.

Acknowledgements The support for these works were provided by QOPNA (FCT UID/QUI/00062/2019), LAQV-REQUIMTE (UIDB/50006/2020), CNC.IBILI (FCT UID/NEU/04539/2019) and CQE (FCT UID/QUI/0100/2019) research units, and to the FCT projects P2020-PTDC/QUI-QOR/31770/2017 and P2020PTDC/QEQ-SUP/5355/2014, through national founds (PIDDAC) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and Internationalization-COMPETE 2020, within the PT2020 Partnership Agreement. J. Calmeiro thanks FCT for her research fellow BI/UI51/7955/2019. References: 1. J. Bazak, J. M. Fahey, K. Wawak, W. Korytowski, A. W. Girotti, Cancer Cell Microenviron. 2017, 4, e1511. 2. a) L. M. O. Lourenço, P. M. R. Pereira, E. Maciel, M. Válega, F. M. J. Domingues, M. R. M. Domingues, M. G. P. M. S. Neves, J. A. S. Cavaleiro, R. Fernandes, J. P. C. Tomé, Chem. Commun. 2014, 50, 8363. b) J. T. Ferreira, J. Pina, C. A. F. Ribeiro, R. Fernandes, J. P. C. Tomé, M. S. Rodríguez-Morgade, T. Torres, J. Mater. Chem. B 2017, 5, 5862. c) J. T. Ferreira, J. Pina, C. A. F. Ribeiro, R. Fernandes, J. P. C. Tomé, M. S. Rodríguez-Morgade, T. Torres, ChemPhotoChem 2018, 2, 640. 3. a) S. D. González, N. Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3621. b) L. M. O. Lourenço, A. Sousa, M. C. Gomes, M. A. F. Faustino, A. Almeida, A. M. S. Silva, M. G. P. M. S. Neves, J. A. S. Cavaleiro, Â. Cunha, J. P. C. Tomé, Photochem. Photobiol. Sci. 2015, 14, 1853.

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Novel biologically active compounds PC50

New glycochlorins for light biomedical applications Sandra Beirão,a,b,c Rosa Fernandes,b,c João P. C. Tomé a a

CQE and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Portugal. b iCBR, Faculty of Medicine, University of Coimbra, Portugal. c CNC.IBILI Consortium, University of Coimbra, Portugal.

Email: sandrabeirao@tecnico.ulisboa.pt

Since its aproval, Photodynamic Therapy (PDT) has been successfully employed in the treatment of various types of tumors1 and, more recently, for the treatment of Age-related Macular Degeneration (AMD), a painless eye condition that affects the macular region of the retina.2 This theraphy results from the combination of three main elements: a chemical compound (photosensitizer, PS), light in the far visible-to-near infrared region and molecular oxygen.3 Tetrapyrrolic macrocycles appear as promising photodynamic agents with applications in several areas. However, it is in clinical PDT that they have been most relevant, due to their capacity to cause oxidative damage of cell components leading to cell death. The PS excitation with specific wavelength of light can generate cytotoxic reactive oxygen species (ROS) from intracellular oxygen.3 The wide diversity of biological functions performed by these molecules demonstrates that minor changes in their base structure may lead to distinct properties. However, their high aggregation tendency and reduced solubility in biological media are very common problems to use them as therapeutic agents. The covalent conjugation of hydrophilic groups with this type of dyes plays an important role in their biocompatibility.4 Their conjugation with specific biomotifs, such as carbohydrates, is a widely used drug synthetic strategy to reach specific biologic targets. The higher specificity has the potential to lead to enhanced PDT efficacy and reduced toxicity of adjacent healthy cells.4 Therefore, the main aim of this work is the bioconjugation of the well-known multifluorinated chlorin derivative ChlF20 with glucose (Glc) and galactose (Gal) moieties (Scheme 1) for cancer and AMD PDT.

Acknowledgements: Support for this work was provided by FCT/MEC to CQE (FCT UID/QUI/0100/2019) and CNC.IBILI (FCT UID/NEU/04539/2019) research units, through national funds and where applicable co-financed by the FEDER, within the PT2020 Partnership Agreement. Sandra Beirão thanks FCT for her Ph.D. scholarship SFRH/BD/140098/2018.

References: 1. S. R. G. Fernandes, R. Fernandes, B. Sarmento, P. M. R. Pereira, J. P. C. Tomé, Org. Biomol. Chem. 2019, 17(10), 2579-2593. 2. H. Deng, T. Li, J. Xie, N. Huang, Y. Gu, J. Zhao, Dye Pigm. 2013, 99, 930-939. 3. P. M. R. Pereira, S. Silva, S.; J. A. S. Cavaleiro, F. A. C. Ribeiro, J. P. C. Tomé, R. Fernandes, Plos One. 2014, 9 (4), e95529. 4. T. F. Ferreira, J. Pina, F. A. C. Ribeiro, R. Fernandes, J. P. C. Tomé, S. M. Rodriguez-Morgade, T. Torres, ChemPhotoChem 2018, 7, 640-654.

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New glycosylated phthalocyanines for cancer photodynamic therapy Sara R. G. Fernandes,a,b,c Bruno Sarmento,b,c,d João P. C. Tomé a a

CQE and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal. b INEB and c i3S, Universidade do Porto, Porto, Portugal. d CESPU, Instituto Universitário de Ciências da Saúde, Gandra, Portugal.

Email: sararfernandes@tecnico.ulisboa.pt

Phthalocyanines (Pcs) and their metal complexes are highly coloured compounds that have been aroused tremendous scientific interest, due to their potential use in various important light applications.1 For example, in biomedicine they have been explored as photosensitizers (PSs) in photodynamic therapy (PDT) and as biomarkers in photodiagnostic.2 For that, Pcs must have the appropriate structural and physicochemical properties. Since the Pc core has low solubility, in almost all common organic solvents and in water, different motifs have been used to increase and modulate their solubility. In this field, glycosylated Pcs have been developed, not only to increase their water stability but also, to give them a biological character, that is an important property in target drugs.1,3 PDT is considered a promising alternative to current treatments against several types of cancer, but its conventional strand is limited by the insufficient efficacy and specificity of first and second generation PSs. Targeted PDT (tPDT) has been developed to create a more cancer-selective PDT approach and has been demonstrating an improved balance between efficacy and toxicity in solid malignancies. This improvement is possible using photobioconjugates, such as glycoconjugates4a,4b and immunoconjugates,5 that utilize strategically their specificity to target overexpressing receptors on malignant cell membranes, while sparing adjacent normal tissues.5 In this communication we will present the preparation and the characterization of new water soluble thioglycosylated Pcs (Scheme 1) which will be subsequently explored to prepare photobioconjugates to target cancer cells through receptor-mediated specificity.

Acknowledgements: Support for this work was provided by FCT through CQE (FCT UID/QUI/0100/2019), INEB (POCI-010145-FEDER-007274) and i3S (POCI-01-0145-FEDER-007274 and NORTE-01-0145-FEDER-000012). Sara Fernandes acknowledges FCT for her Ph.D. scholarship (SFRH/BD/129200/2017). References: 1. A. R. M. Soares, J. P. C. Tomé, M. G. P. M. S. Neves, A. C. Tomé, J. A. S. Cavaleiro, T. Torres, Carbohydr. Res. 2009, 344, 507. 2. L.M.O. Lourenço, D.M.G.C. Rocha, C.I.V. Ramos, M.C. Gomes, A. Almeida, M.A.F. Faustino, F.A.A. Paz, M.G.P.M.S. Neves, A. Cunha, J.P.C. Tomé, ChemPhotoChem 2019, in press. 3. L.M.O. Lourenço, M.G.P.M.S. Neves, J.A.S. Cavaleiro, J.P.C. Tomé, Tetrahedron 2014, 70, 2681. 4. a) P. M. R. Pereira, S. Silva, J. S. Ramalho, C. M. Gomes, H. Girão, J. A. S. Cavaleiro, C. A. F. Ribeiro, J. P. C. Tomé, R. Fernandes, Eur. J. Cancer 2016, 68, 60; b) P. M. R. Pereira, S. Silva, M. Bispo, M. Zuzarte, C. Gomes, H. Girão, J. A. S. Cavaleiro, C. A. F. Ribeiro, J. P. C. Tomé, Bioconjugate Chem. 2016, 27, 2762 5. S.R.G. Fernandes, R. Fernandes, B. Sarmento, P.M.R. Pereira, J.P.C. Tomé, Org. Biomol. Chem. 2019, 17, 2579.

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Synthesis of new phenolic cinnamic acid derivatives and SAR evaluation of their COX-1 and COX-2 inhibitory effects in human blood Daniela Ribeiro, a Carina Proença,a Carla Varela, b,c João Janela, b Elisiário J. Tavares da Silva, b,c Fernanda M. F. Roleira, b,c Eduarda Fernandes a a LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. b Pharmaceutical Chemistry Laboratory, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. c CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal Email: dsribeiro@ff.up.pt

Phenolic cinnamic acid derivatives are known in drug design as remarkable scaffolds for the development of biologically active compounds.1 Despite their anti-inflammatory potential, systematic structure-activity relationships (SAR) studies on their inhibition of prostaglandins (PGs) production, via cyclooxygenase (COX)-1 versus COX-2 are scarce. PGs are inflammatory mediators produced by the constitutive enzyme COX-1 and by the primarily enzyme induced during the inflammatory process, COX-2. Inhibition of PGs synthesis offers a therapeutic approach for the reduction of inflammatory symptoms and the progression of inflammation related diseases. Thus, the search for new compounds that display this type of activity is still needed due to the adverse effects associated with the drugs that are currently and more commonly used to treat inflammation. The aims of this work were to design and synthesize new phenolic cinnamic acid derivatives (Scheme 1), and evaluate their inhibition of PGs production, via COX-1 and COX-2, in human whole blood. Additionally, a correlation of their activities with their theoretical log P values and plasma protein binding prediction were carried out. Finally, from the whole obtained results, new SAR was established. From the synthesized compounds, three new selective inhibitors of COX-2 were found. The presence of two hydrophobic tert-butyl groups and a hydroxyl group in a tri-substituted aromatic ring produced this selectivity and the highest COX-2 inhibitory activities in this study. In conclusion, in this work new promising hit compounds were found, which could be optimized in order to attain new selective COX-2 inhibitors to be used as anti-inflammatory drugs.

Scheme 1: General synthesis of n-hexylamides (secondary amides) and a diethylamide (tertiary amide) of hydroxycinnamic acids. Reagents and conditions: (i) DMF (dimethylformamide), TEA (triethylamine), BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), dichloromethane, rt..

Acknowledgements: This work received financial support from the European Union [FEDER funds through the Operational Competitiveness Program (COMPETE) POCI-01-0145-FEDER-029253 - Projeto 029253]. References: 1. E.J. Tavares-da-Silva, C.L. Varela, A.S. Pires, J.C. Encarnação, A.M. Abrantes, M.F. Botelho, R.A. Carvalho, C. Proença, M. Freitas, E. Fernandes, F.M.F. Roleira, Bioorg. Med. Chem. (2016) 24, 3556.

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SCTC: a new orally active heparin mimetic Ricardo Cristelo,a Catarina Carvalho,a Bárbara Duarte,b Franklim Marques,b Salomé G. Monteiro,d Manuela Morato,d Emília Sousa,a,c Marta Correia da Silva,a,c* Madalena Pintoa,c a Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Portugal. bLaboratório de Análises Clínicas, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto. cCentro Interdisciplinar de Pesquisa Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Portugal. dLaboratório de Farmacologia, Departamento de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade do Porto, Portugal.

Email: m_correiadasilva@ff.up.pt

Due to the limitations of anticoagulants in therapy, the search for new agents is still a medical need.1-2. In our group the persulfate derivative of the naturally-occurring coumarin esculin was synthesized and shown to prolong the clotting times in human plasma.3 More recently, a publication by Ahmad et al. refers that our previously synthesized persulfated esculin, was also active in vivo, being able to decrease the thrombus formation when administered in occlusion induced thrombotic rats.4 Therefore, the validation of this lead compound offers an opportunity to further investigate this scaffold in the pursuit of new active anticoagulant agents however with higher potential to be oral bioavailable. In this work, a new sulfated analogue with higher hydrophobicity (SCTC) was synthesized. The synthetic pathway involved 4 steps: propargylation, copper (I)-catalyzed azide-alkyne cycloaddition, deacetylation, and sulfation. SCTS and all intermediates were fully characterized by IR, 1H and 13C NMR techniques. The anticoagulant activity of SCTC was measured ex-vivo in human plasma by the three classical clotting times, activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) and in vivo with a venous thrombosis model approved by the local (179/2017-ORBEA-ICBAS-UP) and national (003511/2018-DGAV) competent authorities. SCTC was able to prolong the three clotting times, however the APTT assay was the most sensitive to the presence of this derivative (APTT2 = ± 200 μM). From these results can be inferred that the mechanism of action for SCTC could be similar to that of heparin. The in vivo study showed that the weight of the FeCl3-associated thrombus induced in mice treated with SCTC by oral gavage was lower than in controls (33% n=5 in each group). Overall, a new orally active heparin mimetic was disclosed in this work. Acknowledgments: Support for this work was provided by the Strategic Funding UID/Multi/04423/2019 and under the Project POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and ERDF by FCT and by iinfacts, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde.

References: 1.Carvalhal, F.; Cristelo, R. R.; Resende, D. I.; Pinto, M. M.; Sousa, E.; Correia-da-Silva, M., Antithrombotics from the Sea: Polysaccharides and Beyond. Marine drugs 2019, 17 (3), 170. 2.Neves, A. R.; Correia-da-Silva, M.; Sousa, E.; Pinto, M., Structure–activity relationship studies for multitarget antithrombotic drugs. Future medicinal chemistry 2016, 8 (18), 2305-2355. 3.Correia-da-Silva, M.; Sousa, E.; Duarte, B.; Marques, F.; Cunha-Ribeiro, L. M.; Pinto, M. M., Dual anticoagulant/antiplatelet persulfated small molecules. European journal of medicinal chemistry 2011, 46 (6), 2347-2358. 4.Ahmad, I.; Sharma, S.; Gupta, N.; Rashid, Q.; Abid, M.; Ashraf, M. Z.; Jairajpuri, M. A., Antithrombotic potential of esculin 7, 3′, 4′, 5′, 6′-O-pentasulfate (EPS) for its role in thrombus reduction using rat thrombosis model. International journal of biological macromolecules 2018, 119, 360-368.

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Chalcone versus flavone derivatives with in vivo anti-settlement activity Daniela Pereira,ab Catarina Gonçalves,b Beatriz T. Martins,a Ana R. Franco,a Madalena Pinto,a,b Joana R. Almeida,b Marta C. Silva,a,b* Honorina Cidadea,b* a Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal. bCentro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n 4450-208 Matosinhos, Portugal

Email: m_correiadasilva@ff.up.pt; hcidade@ff.up.pt

Biofouling is a natural process resulting in the accumulation of marine micro and macroorganisms, such as bacteria, fungi, algae and invertebrate species on submerged surfaces. This process causes material and economical concerns in marine operations, as well as environmental problems due to the spread of invasive species. Although paints containing antifouling compounds is a commonly strategy to prevent marine biofouling, due to the toxicity of the biocides, such as tributyltin, these paints were banned, so the research for new antifouling compounds is an urgent demand.1,2 Recently, our group has identified some flavonoids with antifouling activity.3,4 Based on this, a series of fourteen structures related with flavones and chalcones was synthesized to evaluate the influence of the referred scaffolds in the antifouling activity. Chalcones were synthesized through Claisen-Schmidt condensation of appropriately substituted acetophenones with benzaldehydes. The synthetic approach for the synthesis of flavones was based on the reaction between phloroglucinol and β-ketoesters, the Mentzer Pyrone synthesis.5 Antifouling screening was performed using the in vivo settlement of mussel (Mytilus galloprovincialis) larvae bioassay.2,3 The most potent compounds were further tested for general ecotoxicity using the brine shrimp (Artemia salina) nauplii lethality test.2,3 Studies of structure-activity relationship allowed to conclude that chalcones showed higher capacity to inhibit the adhesion of mussel larvae than flavones. This work reinforces the relevance of obtain novel chalcone derivatives in order to generate new non-toxic antifoulants to prevent marine biofouling.

Acknowledgements: Support for this work was provided by the Strategic Funding UID/Multi/04423/2019 and under the project PTDC/AAG-TEC/0739/2014 (reference POCI-01-0145-FEDER-016793) supported through national funds provided by FCT and ERDF through the COMPETE - POFC programme and the Project 9471RIDTI. Daniela Pereira acknowledge for her grant (SFRH/BD/147207/2019).

References: 1. K. L. Wang, Z. H. Wu, Y. Wang, C.Y. Wang, Y. Xu, Mar. Drugs 2017, 15, 266. 2. C. Vilas-Boas, E. Sousa, M. M. M Pinto, M. Correia-da-Silva, Biofouling, 2017, 33, 927-942. 3. J. R. Almeida, J. Moreira, D. Pereira, S. Pereira, J. Antunes, A. Palmeira, V. Vasconcelos, M. Pinto, M. Correia-da-Silva, H. Cidade, Science of The Total Environment 2018, 643, 98-106. 4. J. R. Almeida, M. Correia-da-Silva, E. Sousa, J. Antunes, M.Pinto, V. Vasconcelos, I. Cunha, Scientific Reports, 2017, 7, 42424. 5. J. A. Seijas, M. P. Vázquez-Tato, R. Carballido-Reboredo, J. Org. Chem., 2005, 70, 2855-2858.

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Novel biologically active compounds PC55

Improving problematic antibiotics with safe metals: a combined structural and antimicrobial study of new nalidixic acid-Ca(II) frameworks Catarina Bravo,a,b Paula C. Alves,a,b Patrícia Rijo,c,d Vânia André,a,b a Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. b Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento (IST-ID), Av. Rovisco Pais 1, 1049-003 Lisboa, Portugal. c Universidade Lusófona’s Research Center for Biosciences and Health Technologies (CBIOS), Campo Grande 376, 1749-024 Lisboa, Portugal. d Research Institute for Medicines (iMed. ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.

Email: catarinabravo6@gmail.com

Despite the wide availability of antibiotics, infectious diseases are still a leading cause of death worldwide. This issue has been growing due to the increase of multidrug-resistant pathogenic bacteria. Multiresistant bacteria are a challenging problem in the development of new biologically active antibacterial drugs, and it has been inciting a search for new pharmaceutical approaches to overcome it. One of these approaches is altering the composition of an already known antibiotic.1 Nalidixic acid was the first quinolone antibiotic used to treat urinary tract infections caused mostly by Gram-negative bacteria. Nowadays it is no longer used as it has shown bioavailability issues and in some cases acquired bacterial resistance issues. Coordination of different metals to this drug have already proven to improve its activity, by not only changing its physicochemical properties, but also its way of action. The use of safe endogenous metals in particular, such as Mg(II), Zn(II) and Ca(II), is a strategic method with lower toxicity to improve the drug’s efficiency. In addition, biologically active antibiotic coordination frameworks present several advantages, such as controlled drug delivery and synergetic effect from both the metal and the drug itself.1,2 Herein we present a novel family of frameworks incorporating Ca(II) and nalidixic acid, synthesized via mechanochemistry, an environmental-friendly synthetic technique (Scheme 1).These compounds have been fully characterized through single crystal and powder X-ray diffraction, Fourier-transform infrared spectroscopy, thermogravimetry and differential scanning calorimetry analysis and Hirshfeld surface analysis. The antimicrobial activity of the compounds is being studied using selected model organisms, such as yeasts and bacteria.

Ca(II) salt

New compounds with improved activity

Scheme 1: Mechanochemical synthesis of new frameworks incorporating nalidixic acid and Ca(II) Acknowledgements: Authors acknowledge Fundação para a Ciência e a Tecnologia (FCT, Portugal) (projects UID/QUI/00100/2019 and PTDC/QUI-OUT/30988/2017 and contract under DL No. 57/2016 regulation) and FEDER, Portugal 2020 and Lisboa2020 for funding (project LISBOA-01-0145-FEDER-030988). References: 1. a) E. Tacconelli, et al. Lancet Infect Dis. 2018, 18 (3), 318. b) V. André, A. Silva, A. Fernandes, R. Frade, P. Rijo, C. Garcia, A. M. M. Antunes, J. Rocha, M. T. Duarte, ACS Applied Bio Materials 2019, 2(6), 2347. 2. a) C. Bravo, F. Galego, V. André, CrystEngComm 2019, ASAP. b) V. André, F. Galego, M. Martins, Cryst. Growth Des. 2018, 18(4), 2067.

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Novel biologically active compounds PC56

Synthesis of novel methyl 3-(het)arylthieno[3,2-b]pyridine-2carboxylates by Suzuki–Miyaura cross–coupling and antitumor evaluation Bruna R. Silva,a,b,c Cristina P. R. Xavier,b,c M. Helena Vasconcelos,b,c,d Maria João R. P. Queiroza a Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga; bi3S - Instituto de Investigação Inovação em Saúde, Universidade do Porto, Portugal; cCancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; dFFUP - Faculdade de Farmácia da Universidade do Porto, Portugal.

Email: mjrpq@quimica.uminho.pt

Recently, we have been interested in the synthesis of thieno[3,2-b]pyridine derivatives functionalized on the thiophene ring and in their potential antitumor activity.1 Herein, using the C-C Pd-catalyzed Suzuki–Miyaura cross-coupling of methyl 3-bromothieno[3,2b]pyridine-2-carboxylate (1), also prepared, with (het)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids, novel methyl 3-(het)arylthieno[3,2-b]pyridine-2carboxylates 2 were synthesized in moderate to high yields (Scheme 1) and were fully characterized.

Scheme 1: Synthesis of methyl 3-(het)arylthieno[3,2-b]pyridine-2-carboxylates 2a-2h.

Their antitumoral potential was evaluated in human tumor cell lines from - pancreatic cancer (PANC1 and BxPC3), non-small cell lung cancer (NCI-H460) and triple negative breast cancer (MDA-MB-231 and MDA-MB- 468) - by the Sulforhodamine B assay. Compounds 2e, 2f and 2h caused growth inhibition in the breast cancer cell lines (with GI50<13μM), without showing much toxicity against the non-tumorigenic cell line MCF12A, at their respective GI50 values. Although further assays are necessary, the flow cytometry analysis following PI staining showed that the furan derivative 2h altered the cell cycle profile of MDA-MB-468 cells by increasing the G2/M phase with concomitant decrease in G0/G1 phase and Western Blot analysis showed an increase in the expression of p21 when cells were treated with 2x GI50 concentration. On the other hand, compound 2e induced DNA damage (increased expression of γ-H2A.X by Western Blot) and decreased tumor size of xenografted MDA-MD-231 cells evaluated by the in ovo CAM (Chick Chorioallantoic Membrane) assay, at its GI50 concentration. Compound 2f did not alter the cell cycle-profile nor induced apoptosis, at the concentrations tested. Acknowledgements: We thank the FCT Portugal for financial support to CQUM (UID/686/2018-2019) and PTNMR also financed by Portugal2020. References: 1. J. M. Rodrigues, P. Buisson, J. M. Pereira, I. M. Pinheiro, T. Fernández-Marcelo, M. H. Vasconcelos, S. Berteina-Raboin, M.- J. R. P. Queiroz, Tetrahedron 2019, 75, 1387-1397.

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Novel biologically active compounds PC57

A novel spiro-β-lactam with potent anti-HIV and anti-plasmodial activity N. Guerreiro Alves,a A. J. S. Alves,a, I. Bártolo,b C. J. V. Simões,a,c M. Prudêncio,d N. Taveira,b T. Pinho e Meloa a b

CQC, Chemistry Department, Faculty of Science and Technology, University of Coimbra, 3004-535 Coimbra, Portugal

Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003

Lisbon, Portugal cBSIM Therapeutics, Instituto Pedro Nunes, 3030-199 Coimbra, Portugal dInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, P-1648-028 Lisbon, Portugal

Email: nuno.g.alves@student.uc.pt

Malaria and HIV are two of the main public health scourges around the globe, affecting millions of people. There is considerable geographic overlap between Plasmodium and HIV, particularly in sub-Saharan Africa, where co-infection is common and contributes to the spread and pathogenesis of both diseases. Thus, new drugs with dual activity against both HIV and Plasmodium are highly desirable, since current therapeutic options are limited and drug resistance is rising globally1. By exploring the reactivity of 6-diazopenicillanates and 6-alkylidenepenicillanates2, Pinho e Melo’s lab recently synthesized three new spiro-β-lactams with potent activity against both HIV and Plasmodium. The most promising molecule, BSS-730A, presents a remarkable median IC50 of 0.015 μM against HIV-1, 0.008 μM against HIV-2 and 0.55 μM against hepatic infection by P. berghei. BSS-730A is active against multi-drug resistant HIV isolates, lacks antibacterial and antifungal activity and shows no cytotoxicity up to 200 μM in TZM-bl cells or in PBMCs. Although the mechanism of action of BSS-730A remains elusive, time-of-addiction experiments suggest that it targets the late stages of the HIV replicative cycle, i.e. the release and/or maturation of the virus particles. Since HIV protease acts on the viral maturation process, BSS-730A’s inhibitory activity against the enzyme was assessed in a single target assay, which revealed that the molecule has no relevant activity against this molecular target. Thus, the observed absence of BSS-730A’s HIV protease inhibitory activity, together with the results of time-of-addition experiments, indicate that the molecule exerts its activity through a mechanism different from those of the currently approved anti-HIV drugs.

Acknowledgements: Nuno Guerreiro Alves acknowledges FCT for his PhD grant (PD/00147/2013 - doctoral programme in Medicinal Chemistry FCT-PhD Program). Coimbra Chemistry Centre (CQC) is supported by FCT and co-funded by FEDER and COMPETE 2020 through project UID/QUI/00313/2019 References: 1 T. S. Skinner-Adams, K. T. Andrews. Trends Parasitol. 2008 24(6), 264. 2 a) B.S. Santos, T.M.V.D. Pinho e Melo. Eur. J. Org. Chem, 2013, 3901. b) B.S. Santos, T.M.V.D. Pinho e Melo. Tetrahedron, 2014, 70, 3812.

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Design, synthesis and antimicrobial activity of potential modulators of bacterial efflux pumps Fernando Durãesa,b, Filipa Barbosaa,b, Joana Freitas-Silvab,c, Madalena Pintoa,b, Eugénia Pintob,d, Paulo Costab,c, Emília Sousaa,b a

Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, Portugal bInterdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Portugal cICBAS – Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal dLaboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Portugal

Email: esousa@ff.up.pt

The overexpression of efflux pumps (EP) can lead to multidrug resistance, either in humans1 and microorganisms2. This makes EPs suitable targets for potential drug discovery in order to fight the global problem of antimicrobial resistance. In fact, these pumps, ubiquitous to bacteria and fungi, have been extensively studied in the past few years and, although some progress has been achieved, no EP inhibitor has been approved in the therapeutic scenario 2, 3. Thioxanthones are heterocyclic compounds with a dibenzo-γ-thiopyrone scaffold. Their capability to display multiple biological properties, as well as their proneness to chemical modifications, make thioxanthones privileged structures 1. Our group has discovered the potential of these compounds as human efflux pump modulators 4. As such, a virtual library of approximately 1000 aminated thioxanthones was designed to discover inhibitors of bacterial efflux pumps, and docking studies were performed against AcrB (E. coli) and cyanobacteria TolC and mammalian P-glycoprotein. The compounds that displayed good docking scores for bacterial efflux pumps and lower scores for P-glycoprotein were selected to be obtained by synthesis. The amination of thioxanthones was performed using a copper-catalysed Ullmann type C – N coupling. With this strategy, a library of novel aminated thioxanthones was obtained with potential to inhibit efflux pumps and revert multidrug-resistance. The structures of the synthetized compounds were determined by 1H and 13C NMR and X-ray crystallography. A screening for antimicrobial activity and antibiotic synergy has been performed for a set of compounds, according to CLSI protocols. The first was performed in Gram-positive bacteria (Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212) and Gramnegative bacteria (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853). Resistant strains were also used (E. coli SA/2, S. aureus 66/1 and E. faecalis B3/101). Antifungal activity was evaluated for reference strains and multidrug-resistant isolates of Candida albicans, Aspergillus fumigatus and Trichophyton rubrum. Minimum inhibitory concentration (MIC) was determined by the broth microdilution assay. Antibiotic synergy assays were performed for the resistant bacteria strains, using cefotaxime for E. coli, oxacillin for S. aureus and vancomycin for E. faecalis. Despite the fact that the majority of compounds did not present antimicrobial activity for the tested strains, some compounds have displayed promising results when used in combination with antibacterial drugs in resistant strains, suggesting activity in resistance mechanisms. Future studies will involve insights into these mechanisms investigating their activity on in E. coli AG100 strain expressing the AcrAB-TolC pump. Acknowledgements: This work was developed under the Strategic Funding UID/Multi/04423/2019 and Project No. POCI-010145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds. Fernando Durães acknowledges his grant (SFRH/BD/144681/2019). References: 1.Palmeira, A.; Vasconcelos, M. H.; Paiva, A.; Fernandes, M. X.; Pinto, M.; Sousa, E., Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones. Biochem Pharmacol 2012, 83 (1), 57-68. 2.Duraes, F.; Pinto, M.; Sousa, E., Medicinal chemistry updates on bacterial efflux pump modulators. Curr Med Chem 2018, 25 (42), 6030-6069. 3.Holmes, A. R.; Cardno, T. S.; Strouse, J. J.; Ivnitski-Steele, I.; Keniya, M. V.; Lackovic, K.; Monk, B. C.; Sklar, L. A.; Cannon, R. D., Targeting efflux pumps to overcome antifungal drug resistance. Future Med Chem 2016, 8 (12), 1485-1501. 4.Paiva, A. M.; Pinto, M. M.; Sousa, E., A century of thioxanthones: through synthesis and biological applications. Curr Med Chem 2013, 20 (19), 2438-2457.

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Structural Insights into the distinct antimicrobial profile of spiroβ- and spiro-ɣ-lactam Américo J. S. Alves, a Nuno G. Alves,a Diana Fontinha,b Inês Bártolo,c Maria I. L. Soares,a Susana M. M. Lopes,a Miguel Prudêncio,b Nuno Taveira,c Teresa M. V. D. Pinho e Meloa a

CQC and Department of Chemistry, Faculty of Science and Technology, University of Coimbra, Rua Larga, 3004- 535, Coimbra, Portugal. b Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade Lisboa, Avenida Professor Egaz Moniz, P-1648-028, Lisboa, Portugal. c Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal

Email: americo.jsa.92@gmail.com

The discovery and development of novel antimicrobial agents with increased bioactivity and stability attracts great interest in the medicinal chemistry. The β-lactam ring is the core structure of important drugs (e. g. penicillins), and it has been shown that some spiro-β-lactams derivatives have a wide range of other biological activities. Furthermore, g-lactams are also interesting scaffolds since this structural core is also present in a wide range of biologically active compounds. Recently, a research on the synthesis and biological evaluation of spiro-β-lactams led to the discovery of lead compounds with remarkable anti-HIV and anti-Plasmodium properties.1 The identification of this novel class of compounds with potent activity against both infectious agents hold great potential in the fight against both AIDS and malaria. Here, we extend our studies to the design, synthesis and investigation of analogues of previously identified lead compounds, in order to investigate structure-activity relationships. The designed structural modulation of biological active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five membered g-lactam ring (Figure 1). The in vitro activity of a wide range of spiro-β-lactams, as well as of the novel spiro-g-lactams, against HIV and Plasmodium, was evaluated. Among these derivatives, we identified compounds with relevant antiHIV and anti-Plasmodium activity.2 Although conformational and superimposition computational studies revealed no significant differences between β- and g-lactam pharmacophoric features, structural modulation did not lead to compounds with similar biological profiles. Our results suggest that the β-lactamic core is a requirement for the activity of these molecules against both HIV and Plasmodium.

Figure 1: General molecular structure of spiro-β-lactams and spiro-g-lactams. Acknowledgements: Thanks are due to Fundação para a Ciência e a Tecnologia (FCT), Portuguese Agency for Scientific Research (Coimbra Chemistry Centre through the project UID/QUI/00313/2019 and grant SFRH/BD/128910/2017). We acknowledge the UCNMR facility for obtaining the NMR data (www.nmrccc.uc.pt). References: 1. Pinho e Melo, T.; Taveira, N.; Prudêncio, M.; Santos, B.; Bártolo, I. “Novel Spiro-Lactam Compounds, Process And Uses Thereof”, Pub. No.: WO/2018/207165 2. Américo J. S. Alves; Nuno G. Alves; Cátia C. Caratão; Margarida I. M. Esteves; Diana Fontinha; Inês Bártolo; Maria I. L. Soares; Susana M. M. Lopes; Miguel Prudêncio; Nuno Taveira; Teresa M. V. D. Pinho e Melo (in press), Curr. Top. Med. Chem. 2019, DOI: 10.2174/1568026619666191105110049.

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Development of new AChE inhibitors Daniela Malafaia,* Telmo Francisco,* Artur M. S. Silva, Hélio M. T. Albuquerque LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. * Equal contribution to this work Email: helio.albuquerque@ua.pt

Alzheimer’s disease (AD) is one of the most common forms of dementia.1 This neurodegenerative disorder is especially characterized for the progressive memory loss and cognitive capacity.2 It is thought that the cholinergic system is an important factor in many forms of dementia, due to the important role of acetylcholine (ACh) in cognitive processes.3 Although most of the acetylcholinesterase inhibitors (AChEIs) used in clinical treatment of AD have demonstrated some limitations, recent studies believe that the cholinergic hypothesis continues to have a great potential for drug development.2 Therefore, and since AChEIs can increase ACh levels, improving the psychiatric symptoms of AD, herein we designed and synthesized two new families of compounds: i) chromeno[3,4-b]xanthones 1, and ii) fused steroid-dihydropyrans 2.3–5 Both families of compounds were synthesized following simple and straightforward two-step routes, starting from different substrates. The in vitro AChE inhibitory potential was evaluated using the Ellman’s method, with Donepezil as positive control (Figure 1). The synthetic details, structural characterization and IC50 values of each family of compounds will be presented and discussed in terms of their structure-activity relationship (SAR).

Inhibitio n

Figure 1: Chromeno[3,4-b]xanthones 1 and fused steroid-dihydropyrans 2 as new in vitro AChE inhibitors. Acknowledgements: Thanks are due to University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program, and the European Union (FEDER program) via the financial support to the QOPNA research project (FCT UID/QUI/00062/2019) to LAQV-REQUIMTE (UIDB/50006/2020), to the Portuguese NMR Network, and to the PAGE project “Protein aggregation across the lifespan” (CENTRO-01-0145FRDER-000003), including H. M. T. Albuquerque Post-Doctoral grant (BPD/UI98/4861/2017).

References: 1. Liu, P.-P., Xie, Y., Meng, X.-Y. & Kang, J.-S. Signal Transduct. Target. Ther. 4, 29 (2019). 2. Wang, H. & Zhang, H. ACS Chem. Neurosci. 10, 852–862 (2019). 3. Ferreira-Vieira, T. H., Guimaraes, I. M., Silva, F. R. & Ribeiro, F. M. Curr. Neuropharmacol. 14, 101–115 (2016). 4. Cruz, M. I., Cidade, H. & Pinto, M. Future Med. Chem. 9, 1611–1630 (2017). 5. Khoobi, M. et al. Eur. J. Med. Chem. 68, 260–269 (2013).

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Novel semisynthetic derivatives of madecassic acid with anticancer activity Sara Mouraa, b, Pedro J. M. Sobrala, b, Ana S. C. Valdeiraa, b, c, Emad Darvishic, Girma M. Woldemichaelc, d, John A. Beutlerc, Kirk R. Gustafsonc, Jorge A. R. Salvadora,b a

Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. b Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal. c Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States. d Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, Maryland 21702-1201, United States

Email: spmoura17@gmail.com

Madecassic acid (1) is a naturally occurring pentacyclic triterpenoid found in the traditional medicinal plant Centella asiatica (L.) Urban1.This metabolite is known to possess important pharmacological activities. A recent study reported evidence for an apoptotic effect of 1 in the colon cancer cell line CT262. Compared to some other triterpenoid scaffolds, only a limited number of 1 derivatives are known, and few of these have been investigated with respect to their cytotoxic activity3,4. In order to search for novel antitumor, a series of novel 1 derivatives was synthesized and screened for cytotoxicity activity against the NCI-60 panel of cancer cell lines. All the tested semisynthetic derivatives showed better antiproliferative activities than 1 itself. Among them, compound 29 showed GI50 (50% growth inhibition) values ranging from 0.3 to 0.9 μM against 26 different tumor cell lines and revealed particular selectivity for one colon (COLO 205) and two melanoma (SK-MEL-5 and UACC-257) cell lines at the TGI (total growth inhibition) level. The mode of action of 29 was predicted by CellMiner bioinformatic analysis and confirmed by biochemical and cell-based experiments to involve inhibition of the DNA replication process, particularly the initiation of replication, and disruption of mitochondrial membrane potential. Considering the present results, derivative 29 represents a potential lead for the development of new anticancer agents and merits further investigation5 (Figure 1).

Figure 1. Structure of madecassic acid (1) and its derivative 29 with potential anticancer activity. Acknowledgements: The Portuguese Foundation for Science and Technology (FCT) is gratefully acknowledged for funding A.S.C.V. with research grant SFRH/ BD/75806/2011 and S. M. with research grant SFRH/BD/138674/2018. The present study was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (1ZIABC011470, 1ZIABC011568), and with U.S. federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. J.A.R.S. gratefully acknowledges PT2020 (Programa Operacional do Centro 2020) and the financial support by FEDER (European Regional Development Fund) through the COMPETE 2020 Programme (Operational Programme for Competitiveness and Internationalisation), project CENTRO-010247-FEDER- 003269, drugs2CAD. J.A.R.S. also acknowledges financial support from the University of Coimbra. References: 1.B. Brinkhaus, M. Lindner, D. Schuppan, E. G. Hahn, Phytomedicine 2000, 7, 427−448. 2.H. Zhang, M. Zhang, Y. Tao, G. Wang, B. Xia, J. BUON 2014, 19, 372−376. 3.A. S. C. Valdeira, D. A. Ritt, D. K. Morrison, J. B. McMahon, K. R. Gustafson, J. A. R. Salvador, Front. Chem. 2018, 6, 434. 4.T. Van Loc, Q. Nhu Vo Thi, T. Van Chien, T. Ha Le Thi, P. Thao Tran Thi, T.Z. Van Sung, Naturforsch., B: J. Chem. Sci. 2018, 73, 91−98. 5.A. S. C. Valdeira, E. Darvishi, G. M. Woldemichael, J. A. Beutler, K. R. Gustafson, J.A.R. Salvador, J. Nat. Prod. 2019, 82, 2094-2105.

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Novel A-ring cleaved glycyrrhetinic acid derivatives with antiproliferative activity Pedro J. M. Sobrala,b, Sara Mouraa,b, Daniela P. S. Alhoa,b, Marta Cascantec,d, Silvia Marinc,d, Jorge A. R. Salvadora,b a

Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. Center for Neuroscience and Cell Biology, 3000-504 Coimbra, Portugal. cDepartment of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain. dCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain b

Email: pedrojmsobral@gmail.com

Glycyrrhetinic acid (GA) is the hydrolyzed metabolite of glycyrrhizin, a major pentacyclic triterpenoid saponin obtained from the roots of licorice, that has been shown to inhibit tumor initiation and proliferation in several cancer cell lines 1. Nevertheless, it lacks potency and selectivity as an antitumor agent 2. In this regard, a series of novel GA derivatives was synthesized via the opening of its A-ring, along with the coupling of an amino acid. The antiproliferative activity of the derivatives was evaluated against a panel of nine human cancer cell lines. Compound 17 was the most active compound, with an IC50 of 6.1 µM on Jurkat cells, which is 17-fold more potent than its parental compound, and was up to 10 times more selective toward that cancer cell line. Further biological investigation in Jurkat cells indicated that compound 17 may act through arresting cell cycle progression at the S phase and inducing of apoptosis 3. (Scheme 1)

Scheme 1: Structure of Glycyrrhetinic acid (GA) and its derivative Compound 17 with potential antiproliferative activity Acknowledgements: Pedro J.M. Sobral thanks Fundação para a Ciência e Tecnologia (FCT) through project PTDC/QEQMED/7042/2014. Daniela P. S. Alho thanks FEDER (Programa Operacional Factores de Competitividade—COMPETE 2020) and Fundação para a Ciência e Tecnologia (FCT) through Projecto Estratégico: UID/NEU/04539/2013 and the financial support for the PhD grant SFRH/BD/66020/2009. Jorge A. R. Salvador thanks PT2020 (Programa Operacional do Centro 2020), project nº 3269, drugs2CAD, and the financial support by FEDER (European Regional Development Fund) through the COMPETE 2020 Programme (Operational Programme for Competitiveness and Internationalisation). Jorge A. R. Salvador also wishes to thank Universidade de Coimbra for financial support. Marta Cascante and Silvia Marin thank MINECO-European Commission FEDER—Una manera de hacer Europa (SAF2017-89673-R) and Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR)—Generalitat de Catalunya (2017SGR1033). Marta Cascante also acknowledges the support received through the prize “ICREA Academia” for excellence in research, funded by ICREA Foundation—Generalitat de Catalunya. The authors acknowledge UC-NMR facility, which is supported by FEDER and FCT funds through the grants REEQ/481/QUI/2006, RECI/QEQ-FI/0168/2012, and CENTRO-07-CT62-FEDER-002012, and Rede Nacional de Ressonância Magnética Nuclear (RNRMN), for NMR data. References: 1. D.H. Cao, J. Jiang; D. Zhao, M.H. Wu, H.J. Zhang, T.Y. Zhou, T. Tsukamoto, M. Oshima, Q. Wang, X.Y. Cao, Eur. J. Inflamm. 2018, 16, 7 2. R. Wang, Y. Li, X.D. Huai, Q.X. Zheng, W. Wang, H.J. Li, Q.Y. Huai, Drug Des. Dev. Ther. 2018, 12, 1321–1336 3. D.P.S. Alho, J.A.R. Salvador, M. Castante, S. Marin, Molecules, 2019, 24, 2938

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Antibiotic coordination frameworks targeting improved activity - a tactic to rejuvenate “old” quinolone antibiotics Vânia André,a,b Catarina Bravo,a,b Paula C. Alves,a,b Sílvia Quaresma,a M. Teresa Duarte,a Alexandra M. M. Antunes,a Patrícia Rijoc,d a Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. b Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento (IST-ID), Av. Rovisco Pais 1, 1049-003 Lisboa, Portugal. c Universidade Lusófona’s Research Center for Biosciences and Health Technologies (CBIOS), Campo Grande 376, 1749-024 Lisboa, Portugal. d Research Institute for Medicines (iMed. ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.

Email: vaniandre@tecnico.ulisboa.pt

Bactericidal agents, including antibiotics, drastically reduced the number of deaths caused by infections over the last 70 years. However, due to their misuse and abuse, many microorganisms developed resistance mechanisms, causing only in Europe approximately 25000 deaths/year, an economic burden over 1.5 bilion € and productivity losses. Thus, there is a growing concern about the proliferation of these multi-resistant microorganisms against which the antibiotics have become less effective and this is indeed one of the great challenges of today’s society. Bearing in mind that it is imperative to find alternatives to fight this problem, we propose to rejuvenate old antibiotics by developing new metal-organic frameworks of antibiotics (ACFs) to increase their solubility and consequently bioavailability, trying simultaneously to explore synergetic effects with safe metals to increase their antibacterial efficacy. ACFs proposed herein may also be a viable way for a more controlled delivery and release of antibiotics. We have shown that it is possible to enhance the antibacterial activity of quinolone antibiotics by coordinating them to metals like Zn, Mg, Mn, Ag, Ca and Cu (Figure 1).1 These novel compounds are fully characterized. Another important point of this project is that mechanochemistry is the main synthetic pathway proposed. This is an environment-friendly approach that combines the drastically reduction of the amount of solvents, with short reaction times, high yields and high purity.2

Figure 1: General representation of the mechanochemical synthesis of quinolone antibiotics (left), yielding new framework compounds with improved antibacterial activity (right, adapted from reference 2b)

Acknowledgements: Authors acknowledge Fundação para a Ciência e a Tecnologia (FCT, Portugal) (projects UID/QUI/00100/2019 and PTDC/QUI-OUT/30988/2017 and contract under DL No. 57/2016 regulation) and FEDER, Portugal 2020 and Lisboa2020 for funding (project LISBOA-01-0145-FEDER-030988). References: 1. a) V. André, F. Galego, M. Martins, Cryst. Growth Des. 2018, 18(4), 2067. b) V. André, A. Silva, A. Fernandes, R. Frade, P. Rijo, C. Garcia, A. M. M. Antunes, J. Rocha, M. T. Duarte, ACS Applied Bio Materials 2019, 2(6), 2347. c) C. Bravo, F. Galego, V. André, CrystEngComm 2019, ASAP. 2. a) V. André, A. Hardeman, I. Halasz, R. S. Stein, G. J. Jackson, D. G. Reid, M. J. Duer, C. Curfs, M. T. Duarte, T. Friščić, Angew. Chem. Int. Ed. 2011, 50, 7858. b) V. André, S. Quaresma, J. L. Ferreira da Silva, M. T. Duarte, Beilstein Journal of Organic Chemistry 2017, 13, 2416.

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Antibacterial hydrogen-bonding frameworks of pipemidic acid complexes Paula C. Alves a,b,*, Catarina Bravo a,b, Patrícia Rijo c,d, Vânia André a,b a Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; b Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento (IST-ID), Av. Rovisco Pais 1, 1049-003 Lisboa, Portugal; c Universidade Lusófona’s Research Center for Biosciences and Health Technologies (CBIOS), Campo Grande 376, 1749-024 Lisboa, Portugal; d Research Institute for Medicines (iMed. ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.

*Email: paula.alves.marques@tecnico.ulisboa.pt

Antimicrobial resistance to multiple drugs1 is a current threat to public health that has been challenging the scientists. Among the several strategies that have already been applied to overcome this issue, there is the modification of already known molecules2,3, in order to increase their antimicrobial activity. Quinolone antibiotics4, such as pipemidic acid (see Scheme 1), display broad activity spectrum and safety profile which allow their use as antibacterial agents. Nevertheless, it has been reported that microorganisms rapidly adapt and acquire resistance to these compounds5. One valid strategy we are exploring to overcome this problem is the coordination of biocompatible metals to antibiotics6,7. The synthesis of these novel bioactive metal-organic frameworks3 can be successfully attained by mechanochemistry4,5,8,9,10,11 – a green technique for synthesis in the solid state, due to its reduced reaction times, lack of solvent, selectivity enhancement and novel reactivity. Herein we disclose three isostructural hydrogen-bonding frameworks with manganese, zinc and calcium. These frameworks are fully characterized and they are, overall, more active against Escherichia coli and Staphylococcus aureus than pipemidic acid alone.

Scheme 1: Schematic representation of the strategy applied to increase antimicrobial activity of pipemidic acid.

Acknowledgements: We thank Fundação para a Ciência e a Tecnologia (FCT, Portugal) (projects UID/QUI/00100/2019 and PTDC/QUI-OUT/30988/2017 and contract under DL No. 57/2016 regulation) and FEDER, Portugal 2020 and Lisboa 2020 for funding (project LISBOA-01-0145-FEDER-030988). References: 1.J. Davies and D. Davies, Microbiol. Mol. Biol. Rev., 2010, 74(3), 417-433. 2.K. D. Mjos and C. Orvig, Chem. Rev., 2014, 114(8), 4540-4563. 3.V. André and S. Quaresma, in Metal-Organic Frameworks, ed. F. Zafar, InTechOpen, 2016, ch. 7, pp. 135156. 4.M. I. Andersson and A. P. MacGowan, J. Antimicrob. Chemother., 2003, 51, Suppl. S1, 1–11. 5.T. Köhler and J. C. Pechère, in The Quinolones, ed. V. T. Andriole, Academic Press, San Diego, 3rd edn, 2000, ch.4, pp. 139-167. 6.C. Bravo, F. Galego, V. André, CrystEngComm, 2019, ASAP (DOI: 10.1039/C9CE01057B). 7.V. André, F. Galego and M. Martins, Crystal Growth & Design, 2018, 18(4), 2067–2081. 8.V. André, A. Hardeman, I. Halasz, R. S. Stein, G. J. Jackson, D. G. Reid, M. J. Duer, C. Curfs, M. T. Duarte and T. Friščić, Angew. Chem. Int. Ed., 2011, 50, 7858-7861. 9.J. L. Howard, Q. Cao and D. L. Browne, Chem. Sci., 2018, 9, 3080-3094.

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Engaging isatins in multicomponent reactions – Ugi adducts with promising biological activity Pedro Brandão,a,b Mafalda Laranjo,c Filomena Botelho,c Anthony J. Burke,a Marta Pineirob a Department of Chemistry and Centro de Química de Évora – LAQV-REQUIMTE, University of Évora, 7000-671 Évora, Portugal. b CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal. c Biophysics Institute and Institute for Clinical and Biomedical Research (iCBR), area of Environment Genetics and Oncobiology(CIMAGO), Faculty of Medicine and CNC.IBILI Consortium, University of Coimbra, 3004-548 Coimbra, Portugal

Email: pbrandao@qui.uc.pt

The quest for new drug-like and bioactive molecules is one of the main goals of medicinal chemists. By using multicomponent reactions (MCR) combined with privileged structures in Medicinal Chemistry, this goal can be achieved using short and green synthetic routes. Merging the Ugi 4 component reaction (U4CR)1 and the oxindole scaffold, provides a potential methodology to achieve this purpose. The U4CR involves a carbonyl compound, a primary amine, an isocyanide and a carboxylic acid allowing wide variability of substituents at the final peptide-like structure. Furthermore, oxindole derivatives present a wide range of biological activities and are present in the structure of several commercialized drugs. One of the most studied oxindoles is isatin (2,3dioxoindoline), extensively used in drug discovery plataforms.2 In this work, we explore the potential of the carbonyl moiety at position 3 of isatin to develop a new library of isatin-based Ugi adducts, through an InCl3 catalyzed U4CR. This catalyst has been applied in the Ugi reaction, using aldehydes as the carbonyl compound.3 The optimization of the reaction conditions by means of adjustments in the: solvent, temperature, time and catalyst, as well as the purification methodology (chromatography-free) has been explored in order to obtain the desired compounds in a “green by design” manner. The scope of the reaction was evaluated with alkyl and aryl amines, cyclic and sterically hindered isocyanides, halogenated carboxylic acids and several isatin derivatives, allowing the preparation of a small library. The drug-like properties of the resulting products were assessed using a well establish web-based tool (SwissADME),4 and their cytotoxicity towards several tumor cell lines has also been evaluated (Scheme 1), showing promising results.

Scheme 1: Outline of the synthesis, pharmacokinetic prediction and biological activity evaluation of new oxindole-peptide hybrids. Acknowledgements: We thank the FCT for financial support (Pedro Brandão - PD/BD/128490/2017 – CATSUS FCT-PhD Program; Strategic Projects: UID/QUI/00313/2019-CQC (cofunded by COMPETE2020-UE; UID/QUI/0619/2019-CQE-UE; UID/QUI/00100/2013-CQE-IST), UID/NEU/04539/2013, UID/NEU/04539/2019 and COMPETE-FEDER POCI-01-0145FEDER-007440. References: 1. a) A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083. b) H. Alvim, E. Júnior, B. Neto, RSC Adv. 2014, 97, 54282. 2. a) M. Kaur, M. Singh, N. Chadha, O. Silakari, Eur. J. Med. Chem. 2016, 123, 858. b) P. Brandão, A. J. Burke, Tetrahedron 2018, 74, 4927. 3. P. Brandão, A. J. Burke, Chim. Oggi – Chem. Today 2019, 37, 21. 4. A. Daina, O. Michielin, V. Zoete, Sci. Rep. 2017, 7, 42717

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Water-soluble meso-tetraarylporphyrin derivatives as potential polymeric ligands for theranostic Mariana C. S. Vallejoa, Sofia G. Serra b, Vanda Vaz Serrab, Nuno M. M. Mouraa, M. Graça P. M. S. Nevesa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. bCentro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal

Email: mariana.vallejo@ua.pt

Porphyrins and related derivatives are highly versatile macrocycles due to their physico- and photochemical features and have been extensively studied in different scientific fields as catalysts, components in new electronic materials, biomimetic models for photosynthesis, (chemo)sensors and as photosensitizers in medicine.1 Porphyrins have been intensively investigated in photodynamic therapy (PDT), a therapeutic methodology applied on the treatment of cancer and retina macular degeneration. PDT combines three components: light, molecular oxygen and a photosensitizer (PS). Malignant and abnormal cells are destroyed by singlet oxygen and by reactive oxygen species that are generated by a photosensitive drug (photosensitizer) when light of appropriate wavelength is applied.2 Cancer theranostic is an attractive application for this family of compounds, that combines the simultaneous diagnostic and treatment, and has received a significant effort by the scientific community in the last years.3 New and better applications require new compounds and meso-tetraarylporphyrins play an important role as key starting building blocks for further functionalizations and modulation of their physico-chemical features to improve fluorescence quantum yields and Stokes shifts, and reduce aggregation in physiological media.4 Following our interest on the preparation of tetrapyrrolic derivatives with potential application in PDT/theranostic, in this communication, it will be presented and discussed the synthesis and the characterization of a series of water soluble meso-substituted tetraarylporphyrins (Figure. 1) to be incorporated on potential carriers/delivery systems for the development of new materials for theranostic.

Figure 1: General structure of water soluble meso-tetraarylporphyrins. Acknowledgements: We thank the University of Aveiro and FCT/MCT for the financial support for QOPNA research Unit (FCT UID/QUI/00062/2019), LAQV-REQUIMTE (UIDB/50006/2020) and the FCT project THERMIC (PTDC/QUICOL/29379/2017), through national founds and were co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. The research grants of M.C.S. Vallejo (REF: BI-UI51-8642-2019) and S.G. Serra are supported by the project THERMIC (PTDC/QUI-COL/29379/2017), and the research contracts of N.M.M. Moura (REF.-04888-ARH/2018) and Vanda Vaz Serra are funded by national funds (OE), through FCT. References: 1 A. F. R. Cerqueira, N. M. M. Moura, V. V. Serra, M. A. F. Faustino, A. C. Tomé, J. A. S. Cavaleiro, M. G. P. M. S. Neves, Molecules, 2017, 22, 1269. 2 R. Bonnett, Chemical Aspects of Photodynamic Therapy; Gordon and Breach Science Publishers: London, 2000. 3 E.-K. Lim. T. Kim, S. Paik, S. Haam, Y.-M. Huh, K. Lee, Chem. Rev., 2015, 115, 327. 4 S. Singh, A. Aggarwal, N. V. S. D. K. Bhupathiraju, G. Arianna, K. Tiwari, C. M. Drain, Chemical. Rev., 2015, 115, 10261. .

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Synthesis of molecular probes with a sulfonamide moiety Bruno Franco, J. Macara, Luís C. Branco, M. Manuel B Marques LAQV@REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica (Portugal) Email: b.franco@campus.fct.unl.pt

Sulfonamides have a broad variety of applications ranging from pharmaceutical to biological active compounds, polymers and even pesticides.1 Sulfonamides constitute an important class of compounds in pharmaceutical industry since they possess several biological activities such as antibacterial, antitumor and antithyroid.2 Classical synthetic methods to prepare sulfonamides involve the use of toxic reagents as for example the usage of gaseous SO2, the use of metals and some have poor group functional group selectivity.3 Our group has recently explored a methodology to prepare the sulfonamides, by using an hypervalent iodine group transfer reagent.4 In order to develop novel molecular probes for drugs, proteins or DNA, different sulfonamides have been synthesized using the developed protocol, scheme 1. Herein, we will present the studies on their preparation, fluorescence properties, as well as the emission and absorption spectra in the NIR region.

Scheme 1: Sulfonamide based probes

Acknowledgements: This work was supported by the Associate Laboratory for Green Chemistry- LAQV which is financed by national funds from FCT/MCTES (UID/QUI/50006/2019) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER - 007265). The National NMR Facility is supported by FC&T (ROTEIRO/0031/2013 – PINFRA/22161/2016, co-financed by FEDER through COMPETE 2020, POCI, and PORL and FC&T through PIDDAC). References: 1. Beesley, W. N., & Peters, W. (1971). 1971, 64(4), 897–899. 2 Supuran, C. T. (2017). Special issue: Sulfonamides. Molecules, 22(10). 3. Emmett, E. J. and Willis, M.C. Asian J. Org. Chem. 2015, 4, 602. 4. Poeira, D. L., Macara, J., Faustino, H., Coelho, J. A. S., Gois, P. M. P., & Marques, M. M. B. Eur. J. Org. Chem., 2019, 15, 2695–2701.

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5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin: a versatile platform on the preparation of biologically active photosensitizers A. Sofia Joaquinito,a Cristina J. Dias,a Carlos J. P Monteiro,a Mariana Q. Mesquita,a Maria G. P. M. S. Neves,a Francesco Tessari,b Giorgia Miolo,b M. Amparo F. Faustinoa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. b Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy

Email: a.joaquinito@ua.pt

The advantages of introducing fluorine atoms in biologically active organic molecules has been recognized and documented by scientific community.1 Nowadays, it’s estimated that 20% of pharmaceutical compounds contain at least one fluorine atom once it is well established and understood that the replacement of an hydrogen by a fluorine atom can make an impact on pharmacological features, metabolic stability, biological target selectivity and physical properties. 2 On this field, our research group has been exploring the synthetic versatility of mesopentafluorophenylporphyrins as a flexible platform that can rapidly and efficiently be modified, generating libraries of photo-active compounds with biological interest. In this context, 5,10,15,20tetrakis(pentafluorophenyl)porphyrin has revealed to be a multipurpose template with the ability to be readily converted to chlorin, bacteriochlorin and isobacteriochlorin counterparts, or to be efficiently and selectively derivatized by means of nucleophilic aromatic substitution reactions, devising a plethora of functional groups.3,4 The remaining fluorine atoms enhance the photostability and benefit the ROS generation quantum yield of the dyes. These properties provide these compounds the ideal features to be used as theranostics photosensitizers since they can both generate cytotoxic species, (inactivating microorganism and killing cancer cells) and concomitantly act as contrast agent in Fluorescence or 19F NMR Imaging. In this communication, the functionalization of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin by nucleophilic aromatic substitution will be reported. The structural characterization and photophysical properties of new compounds will be assessed and presented.

Scheme 1 Acknowledgements: The authors thank University of Aveiro and FCT/MCT for the financial support provided to QOPNA research Unit (FCT UID/QUI/00062/2019), to LAQV-REQUIMTE (UIDB/50006/2020) and to the Project PREVINE - FCTPTDC/ASP-PES/29576/2017), through national funds (OE) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and Internationalization-COMPETE 2020, within the PT2020 Partnership Agreement. Thanks are also due to the Portuguese NMR and Mass Networks. References: 1. a) D. E. Yerien, S. Bonesi, A. Postigo, Org. Biomol. Chem. 2016, 14 (36), 8398-8427. b) Y. Zhou, J. Wang, Z. N. Gu, S. N. Wang, W. Zhu, J. L. Acena, V. A. Soloshonok,.K. Izawa, H. Liu, Chem. Rev. 2016, 116 (2), 422-518. 2. D. O'Hagan,. J. Fluor. Chem. 2010, 131 (11), 1071-1081. 3. a) J. I. T. Costa, A. C. Tomé, M. G. P. M. S. Neves, J. A. S. Cavaleiro, J. Porphyrins Phthalocyanines 2011, 15 (11-12), 1116-1133. b) M.Q. Mesquita, J.C.J.M.D.S. Menezes, S.M.G. Pires, M.G.P.M.S. Neves, M.M.Q. Simões, A.C. Tomé, J.A.S. Cavaleiro, A. Cunha, A. L. Daniel-da-Silva, A. Almeida, M. A. F. Faustino, Dyes and Pigments, 2014, 123-133.

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Searching the optical properties of corrole macrocycles as new gasotransmitters chemosensors Rita L. Araújo,a Carla I. M. Santos,a,b , Maria A. F. Faustino,a Maria G. P. M. S. Neves,a José M. G. Martinho,b Ermelinda Maçôas b a

LAQV-Requimte and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. bCQFM, Centro de Química-Física Molecular, IN-Institute of Nanosciences and Nanotechnology, CQE, Centro de Química Estrutural, Instituto Superior Técnico, 1049-001 Lisboa, Portugal. Email: anararaujo@ua.pt

The design of new fluorescent chemosensors is a hot and always actual topic because of important applications in fields as biology and medicine, where molecular probes are often the most useful tools for in vitro and in vivo monitoring of biologically relevant analytes. A fluorescent chemosensor is obtained by merging two fundamental moieties: the recognition site (receptor) and the signalling source (fluorophore).1 Corroles are tetrapyrrolic macrocycles that share close similarities with porphyrins and have useful properties to be considered as fluorophores in this type of applications. They show, in general, strong absorption (> 400 nm) and fluorescence emission (> 600 nm) bands in the visible region of the electromagnetic spectra and high N–H acidity.2 As a part of our research project on the preparation and characterization of new emissive molecular probes, we present here the synthetic access to a new corrole derivative incorporating a nitro group in the macrocycle core that will allow us to explore its interaction with gasotransmiters. The new compound was characterized by NMR-1H, NMR-13C, elemental analysis, UV-vis and fluorescence emission spectroscopy. The preliminary results of the interaction of the nitrocorrole derivative with a gasotransmiter will be also discussed.

Figure 1. Schematic representation of a chemosensor. Acknowledgements: Thanks are due to the University of Aveiro, Instituto Superior Técnico de Lisboa and FCT/MCT for the financial support for the QOPNA (FCT UID/QUI/00062/2019), the LAQV-REQUIMTE (UIDB/50006/2020), CQE-IST (UID/CTM/50011/2019, PTDC/NAN-MAT/29317/2017, PTDC/QUIQFI/29319/2017), through national funds (OE) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and Internationalization-COMPETE 2020, within the PT2020 Partnership Agreement. Thanks are also due to the Portuguese NMR and Mass Networks. C. I. M. Santos acknowledges the research contract (REF.IST-ID/95/2018) funded by national funds (OE), through FCT (Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19). Rita L. Araújo also thanks FCT for her research grant (POCI-01-0145-FEDER-29319) References: 1. C. Lodeiro et al. Chem. Soc. Rev. 2010, 39, 2948-2976. 2. C. I. M. Santos et al. Journal of Materials Chemistry C 2012, 22, 13811.

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1,2,4-Triphenyl-pyrroles: synthesis, structures, and luminescent properties Joana R. M. Ferreira,a Raquel Nunes da Silva,a,b João Rocha,c Artur M. S. Silva,a Samuel Guieua,c a

LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. bInstitute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal. c CICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. Email: joanarmf@ua.pt; sguieu@ua.pt

As a versatile scaffold, pyrrole and its derivatives can be found in different pharmacophores with a wide range of biological activities.1 Due to these characteristics, pyrrole synthesis has gained some attention.2 In particular, the synthesis of pyrroles from chalcones has already been reported.3 In this work, five new pyrroles were synthesized and characterized, according to the synthetical pathway represented in scheme 1. These new pyrroles are decorated with phenyl rings at positions 1, 2 and 4, with electron-donating groups in the para position. Their photophysical properties were then evaluated, demonstrating that there are weakly luminescent in solution. The crystal structure of 4b was also studied in order to understand the photophysical properties of this type of molecules in the crystalline state.

Scheme 1: Synthetic route for compounds 4a-e.

Acknowledgements: Thanks are due to University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program, and the European Union (FEDER program) via the financial support to the QOPNA research project (FCT UID/QUI/00062/2019), to LAQV-REQUIMTE (UIDB/50006/2020), to the IBiMED Research Unit (UID/BIM/04501/2013; UID/BIM/04501/2019), to CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/ 50011/2019, financed by national funds through the FCT/MCTES, to the Portuguese NMR Network, to the ThiMES project (POCI-01-0145-FEDER-016630) and to the PAGE project “Protein aggregation across the lifespan” (CENTRO-01-0145-FRDER-000003), including R. Nunes da Silva PostDoctoral grant (BPD/UI98/6327/2018) Samuel Guieu is supported by national funds (OE), through FCT, I.P., in the scope of the framework contract foreseen in the numbers 4, 5, and 6 of the article 23, of the DecreeLaw 57/2016, of August 29, changed by Law 57/2017, of July 19. References: 1. R. Kaur, S.K. Manjal, R.K. Rawal, K. Kumar, J. Pharm. Chem. Chem. Sci. 2017, 1, 17. 2. a) S.S. Gholap, Eur. J. Med. Chem. 2016, 110, 13; b) F. Cardona, J. Rocha, A.M.S. Silva, S. Guieu S., Dye Pigment 2014, 111, 16. 3. M. J. Hall, S. O. McDonnell, J. Killoran, D. F. O’Shea, J. Org. Chem. 2005, 70, 5571.

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Nanomagnets decorated with tetrapyrrolic macrocycles: shining a light in pathogens inactivation Carlos J. P. Monteiro,a Cristina J. Dias,a Zhi Lin,b Maria G. P. M. S. Neves,a M. Amparo F. Faustinoa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal b CICECO/Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. Email: cmonteiro@ua.pt

Recently, magnetic nanoparticles (MNPs) have been subject of extensive investigation owing to their key properties (e.g. magnetical separability/reusability) for biological applications such as, diagnostic, drug delivery, and light-assisted therapy.1 A challenging issue in the nanomagnetic field is the development of strategies to functionalize these particles. Inorganic materials based on silica are receiving a special attention, from the fact that the silica shell not only protects the magnetic nanoparticles, but also provides a new platform for further functionalization, enlarging the application scope for the MNPs.2 Our research group has been developing tetrapyrrolic macrocycles which are being successfully used as efficient PSs on the photoinactivation of a broad spectrum of pathogens.3 However from a practical viewpoint, the attachment of a PS to an appropriate support is highly desirable, in order to facilitate their removal from the water matrix, allowing further reuse in successive photosensitization cycles. In this communication, the preparation and functionalization of nanostructured magnetic supports, consisting of magnetite nanoparticles coated with an amorphous silica shell will be reported. The resulting particles were modified with appropriate functionalities and cationic porphyrin PSs were covalently immobilized on the MNPs surface. All the prepared photoactive hybrid materials have been characterized.

Scheme 1 Acknowledgements: The authors thank University of Aveiro and FCT/MCT for the financial support provided to QOPNA research Unit (FCT UID/QUI/00062/2019), the LAQV-REQUIMTE (UIDB/50006/2020), the Associate Laboratory CESAM (FCT UID/AMB/50017/2019) and to Project PREVINE - FCT-PTDC/ASP-PES/29576/2017), through national funds (OE) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and Internationalization-COMPETE 2020, within the PT2020 Partnership Agreement. Thanks are also due to the Portuguese NMR and Mass Networks. References: 1. L. Fernandez, W. Borzecka, Z. Lin, R. J. Schneider, K. Huvaere, V. I. Esteves, A. Cunha, J. P. C Tomé, Dyes Pigment. 2017, 142, 535-543. 2. C. M. B Carvalho, E. Alves, L. Costa, J. P. C. Tomé, M. A. F. Faustino, M G.P.M.S. Neves, A. C Tomé, J. A. S. Cavaleiro, A. Almeida, A. Cunha, Z. Lin, J. Rocha, Acs Nano 2010, 4 (12), 7133. 3. M. Q. Mesquita, C. J. Dias, M. Neves, A. Almeida, M. A. F. Faustino, Molecules 2018, 23 (10).

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Synthesis of functional meso-triarylcorroles of A2B type Paula S. S. Lacerda,a,b Maria G. P. M. S. Neves,b Joana F. B. Barataa a

CESAM, University of Aveiro. bLAQV-Requimte and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. Email: placerda@ua.pt

Corroles are aromatic tetrapyrrolic ring-contracted macrocycles and have been attracting considerable attention due to their unique photophysical and chemical properties. In fact, corroles possess key photophysical properties as high excitation coefficients, fluorescent quantum yields, phosphorescence and photostability to be used in different therapeutic applications namely as photosensitizers in photodynamic therapy,1 as contrast agents for biomedical imaging, but also as catalysts2 and sensors.3 The development of new strategies for corrole synthesis and adequate functionalization4 at the β-pyrrolic positions or at the meso positions allow the tuning of these photophysical properties for a specific application. Following our interest in the surface functionalization of nanoparticles with key functional corroles,5 in this communication we will report the synthesis and structural characterization of key functional meso-triarylcorroles of A2B type (Figure 1) bearing aryl groups adequately substituted with CN, COOH and Py functionalities to be anchored on the surface of nanoparticles.

Figure 1 Acknowledgements: We thank FCT/MCTES for the financial support to CESAM (UID/AMB/50017/2019), through national funds, to the University of Aveiro and FCT/MCT for the financial support for the QOPNA research Unit (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. This work was supported by the project [Corlutna (POCI-01-0145-031523)] funded by FEDER, through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI), and by national funds (OE), through FCT/MCTES. References: 1. R. D. Teo, J. Y. Hwang, J. Termini, Z. Gross, H. B. Gray, Chem. Rev. 2017, 117, 2711. 2. W. Zhang, W. Lai, Cao, R. Chem. Rev. 2017, 117, 3717. 3. R. Paolesse, S. Nardis, D. Monti, M. Stefanelli, C. Di Natale, Chem. Rev. 2016, 117, 2517. 4. a) Barata J. F. B., Neves M. G. P. M. S., Faustino M. A. F., Tomé A. C., Cavaleiro J. A. S. Chem. Rev. 2017, 117, 3192. b) Orłowski, R., Gryko D., Gryko D. T. Chem. Rev. 2017, 117, 3102. 5. a) R. P. Pereira, T. Trindade, J. F. B. Barata, Magnetochemistry 2018, 4, 37. b) J. F. B. Barata, A. L. Daniel-Da-Silva, M.G.P.M.S. Neves, J.A.S. Cavaleiro, T. Trindade, RSC Advances 2013, 3, 274.

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Evaluation of the gas-phase fragmentation pattern of new derivatives obtained from the reaction of β-nitro-meso-tetraphenylporphyrin with p-chlorophenoxyacetonitrile Catarina I.V. Ramos,a Mohammed Eddahmi,a,b Nuno M.M. Moura,a Latifa Bouissane,b M. Amparo F. Faustino,a José A.S. Cavaleiro,a El Mostapha Rakib,b Maria G.P.M.S. Nevesa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal bLaboratory of Organic and Analytic Chemistry, Faculty of Sciences and Technics, Sultan Moulay Slimane University, BP 523, 2300 Beni-Mellal, Morocco. Email: gneves@ua.pt

meso-Tetraarylporphyrins bearing primary groups (e.g. formyl, nitro) at meso or beta positions are excellent templates to modify the porphyrinic macrocycle.1-3 In particular, βnitro-meso-tetraarylporphyrins can be used in different synthetic approaches like nucleophilic or electrophilic substitutions, nucleophilic addition, cycloaddition reactions and reduction.3 Following our interest in the β-modification of meso-tetraarylporphyrins, we decided to revisit the reaction of p-chlorophenoxyacetonitrile using the free-base βnitro-meso-tetraphenylporphyrin aiming to obtain product 1 from the cyanomethylation at the β-pyrrolic carbon adjacent to the nitro unit (Figure 1). To our surprise, the absence of a metal in the inner core of the macrocycle gave rise to a different reaction profile, and depending on the experimental conditions used, the products 2 and 3 were obtained. The gas-phase fragmentation pattern of the new derivatives was evaluated by ESI-MS (electrospray mass spectrometry) and allowed to stablish unequivocally their structures. We will present here the obtained MSn spectra (n=1 to 3) of isolated compounds and the observed fragmentation patterns will be discussed. In some of the fragmentation proposals, reactions involving rearrangement/elimination triggered by the interaction between the meso-phenyl groups and the β-pyrrolic substituents were considered according with previous reports.4

Figure 1. Structures of compounds 1-3. Acknowledgements: Thanks are due to the University of Aveiro and FCT/MCT for the financial support for the QOPNA research Unit (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. The authors also thank the Transnational cooperation programs, FCT-CNRST (Morocco) for financial assistance (2019-2020). C.I.V. Ramos (REF.-047-88-ARH/2018) and N.M.M..Moura (REF.-048-88-ARH/2018) thank University of Aveiro for their research contracts. References: 1. A.F.R. Cerqueira, N. M.M. Moura et al. Molecules 2017, 22, 1269. 2. J.A.S. Cavaleiro, A.C.Tomé, M.G.P.S.Neves. Handbook of Porphyrin Science. In Meso-tetraarylporphyrin derivatives: New synthetic methodologies, K. M. Kadish, K.M.S., R. Guilard Ed. World Scientific Publishing Company Co.: Singapore, 2010; Vol. 2, pp. 193. 3. V.V. Serra, S.M.G. Pires, C.M.A. Alonso, M.G.P.M.S. Neves, A.C.Tomé, J.A.S. Cavaleiro. Meso-Tetraarylporphyrins Bearing Nitro or Amino Groups: Synthetic Strategies and Reactivity Profiles. In Synthesis and Modifications of Porphyrinoids, Paolesse, R., Ed. Springer Berlin Heidelberg: Berlin, Heidelberg, 2014. 4. a) C.I.V. Ramos, N.M.M. Moura et al. Int. J. Mass Spectrom 2015, 392, 164; b) R.A. Izquierdo, Eduarda M. P. Silva, et al. JASMS, 2007, 18, 218; c) E. Silva, M. Domingues, et al. J. Mass Spectrom. 2005, 40, 117.

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Ohmic versus conventional heating in the synthesis of palladium(II) pyrrolidine-fused chlorins Inês Moreira,a José Almeida,a Andreia Leite,a Ana M. G. Silva,a,* Maria Rangelb a

REQUIMTE-LAQV, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal. b REQUIMTE-LAQV, Instituto de Ciências Biomédicas de Abel Salazar, 4099-003 Porto, Portugal. *Email: ana.silva@fc.up.pt

Photodynamic therapy (PDT) involves a light-activated photosensitizer (PS) that reacts with molecular oxygen, giving rise to singlet oxygen (1O2), and reactive oxygen species (ROS), that are toxic to cancer cells. The mode of action of this type of therapy has been studied worldwide and the success of this therapy depends on the ability of the PS to absorb light within the PDT wavelength window (650-850 nm), with a higher penetration of light into tissues. Photosensitizers based on palladium(II) porphyrins have received great attention due to their high quantum yield in what concerns generation of 1O2.1 A mandatory goal in modern synthetic chemistry is to save time and energy while developing efficient reactions, with easily isolated products in high yields. This objective of sustainable chemistry stimulated the use of ohmic heating ( H), an advanced heating process where an AC electrical current is passed into the reaction mixture (aqueous media), which serves as an electrical resistor thus resulting in an uniform and fast heating, which has the possibility of an efficient reaction scale-up.3 We previously performed the metallation of pyrrolidine- and isoxazolidine-fused chlorins2 with zinc(II) and copper(II) salts using H. Herein, we report a comparative study of metallation of the pyrrolidine-fused chlorin with palladium(II) salts using H and conventional heating (CH) (Figure 1), as well as the spectroscopic results of the palladium(II) complexes obtained.

Figure 1: Illustration of the synthesis of palladium(II) pyrrolidine-fused chlorins. Acknowledgements: This work received financial support from the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia), under the Partnership Agreement PT2020 through project UID/QUI/50006/2013-POCI/01/0145/FEDER/007265(LAQV/REQUIMTE) and PTDC/QUI-QOR/29426/2017 (X-Sensors). J. Almeida acknowledges the financial support from the FCT Ph.D. grant (PD/BD/142868/2018). References: 1.M. Obata, S. Hirohara, R. Tanaka, I. Kinoshita, K. Ohkubo, S. Fukuzumi, S. Yano, J. Med. Chem. 2009, 52, 2747. 2.J. Almeida, A. M. N. Silva, S. L. H. Rebelo, L. Cunha-Silva, M. Rangel, B. de Castro, A. Leite, A. M. G. Silva, New J. Chem. 2018, 42, 8169. 3.a) J. Pinto, V. L. M. Silva, A. M. G. Silva, A. M. S. Silva, J. C. S. Costa, L. Santos, R. Enes, J. A. S. Cavaleiro, A. Vicente, J. A. C. Teixeira, Green Chem. 2013, 15, 970. b) V. L. M. Silva, A. M. G. Silva, L. M. N. B. F. Santos, A. M. S. Silva, Boletim da SPQ. 2016, II, 143, 15. b) V. L. M. Silva, A. M. S. Silva, A. M. G. Silva, J. Pinto, R. Enes, J. A. S. Cavaleiro, A. A. M. O. S. Vicente, J. A. C. Teixeira, A. Morais, Reator Para Síntese Química Com Aquecimento óhmico, Método e Suas Aplicações, Portuguese patent No. 105908.

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Lighting-up protein and lipid aggregates Raquel Nunes da Silva,a,b Roberto A. Dias,b Catarina C. Costa,a Mariana J. G. Santos,a Mariana Q. Alves,b Ana Sousa,c Susana S. Braga,a André Maia,d Fatima Camões,b Mónica Almeida,b João Rocha,c Artur M. S. Silva,a Sandra I. Vieira,b Samuel Guieua,c a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal, bIBiMED, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal cCICECO Aveiro-Institute of Materials and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal, dUniversity of Stanford, USA

Email: rsons@ua.pt

The detection of bio-macromolecules, particularly aggregates of lipids or proteins, that are associated with high incidence diseases, is a key issue in both fundamental research studies and medical diagnostics. Push-pull chromophores and luminogenic materials with aggregation-induced emission (AIE) properties have gained importance as dyes in biological studies and diagnostics. In this communication is intended to describe the synthesis and characterization of a group of fluorescent probes with affinity for lipid and protein aggregates. Optoelectronic properties and biological evaluation of the fluorophores will also be presented. As lipid aggregates are concerned, one of the tested dyes1 showed good fluorescence intensity in cells, lipid vesicles, and presented altered emission spectra depending on the polarity of the medium, due to its push-pull character. This fluorophore demonstrated to be suitable for high-content screens for the diagnosis of Farber’s disease, a lysosomal storage disease. Furthermore, a new AIEgen was used as a biological vital dye and proved to be a promising fluorescent probe for the selective staining of protein aggregates, allowing imaging by fluorescence confocal microscopy, with a selectivity comparable to a commercial dye, and for detection of protein aggregates in routine diagnosis (Figure 1).2

Figure 1: a) Structure of the fluorophores. Staining of b) protein aggregates and c) lipid aggregates in cells, as seen using a confocal microscope. Acknowledgements: Thanks are due to University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program, and the European Union (FEDER program) via the financial support to the QOPNA research project (FCT UID/QUI/00062/2019), to the LAQV-REQUIMTE (UIDB/50006/2020), to the IBiMED Research Unit (UID/BIM/04501/2013; UID/BIM/04501/2019), to CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/ 50011/2019, financed by national funds through the FCT/MCTES, to the Portuguese NMR Network, to the ThiMES project (POCI-01-0145-FEDER-016630) and to the PAGE project “Protein aggregation across the lifespan” (CENTRO-01-0145-FRDER-000003), including R. Nunes da Silva Post-Doctoral grant (BPD/UI98/6327/2018). Samuel Guieu is supported by national funds (OE), through FCT, I.P., in the scope of the framework contract foreseen in the numbers 4, 5, and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19. We also thank the LiM facility of iBiMED/UA, a member of the Portuguese Platform of BioImaging (PPBI; POCI-01-0145-FEDER-022122). References: 1. Patent WO/2017/182945 A1 for “Fluorescent cell markers with large Stroke’s shift”. 2. R. Nunes da Silva, C.C. Costa, M. J. G Santos, M. Q. Alves; S. S. Braga, S. I. Vieira, J. Rocha, A. M. S. Silva, S.Guieu Chem. Asian J. 2019, 14, 859.

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Synthesis of potentially bioactive pyrazolidin-3-ones derivatives for the treatment of bipolar disorder M. Gomes,a J. M. Pinheiro,a J. A. Figueiredo,a S. Silvestre,b M. I. Ismaela a

Departamento de Química, Universidade da Beira Interior, FibEnTech, Covilhã, Portugal. bCICS-UBI – Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal Email: iismael@ubi.pt

Bipolar disorder, also known as manic-depressive illness, is a serious, chronic, and incapacitating neuropsychiatric disorder in which the patient has recurrent episodes of two opposing mood states, mania and depression. Between the conventional therapeutic approaches is the prescription of Lithium Carbonate which has serious side effects or the prescription of a mixture of antidepressants and antipsychotics, in which the first is used to treat depressive crisis and the second ones to treat manic episodes.1-4 Because of the lack of efficacy of the treatments available and the various side effects, it is crucial to design new molecules with potential for the treatment of this illness.5-7 Carbohydrate derivatives have shown interesting pharmacological activities for the treatment of several illnesses, including neurological diseases, and consequently have gained ground in the pharmaceutical industry over the last few years7,8 Therefore, the aim of this work is to design and carbohydrate derivatives, namely pyrazolidin-3-ones, with potential interest in the treatment of bipolar disorder and further in vitro biological evaluation. The synthesis of the pyrazolidin-3-ones started with a commercially available compound, 1,2:5,6-Di-Oisopropylidene-α-D-glucofuranose. Several reactions were performed until an aldehyde group at position 5 of the furanos idic ring was obtained. Then, an α,β-unsaturated ester by a Wittig reaction was prepared, which is the final precursor to the reaction in which the ring is closed to afford the pyrazolidin-3-one system.9,10 The in vitro cytotoxicity assays performed shows that the compounds present no relevant cytotoxicity in normal human dermal fibroblasts and on the neuronal N27 cell line and therefore other biological evaluations to assess their potential interest as anti-bipolar agents can be considered.10 References: 1. J. W. Young; D. Dulcis, Eur. J. Pharmacol. 2015, 759, 151–162. 2. R. Machado-Viera, H. Manji, C. A. Zarate Jr Bipolar Disord. 2009, 11 (Suppl. 2), 92–109. 3. T. Kato, M. Kubota, T. Kasahara, Neurosci. Biobehav. Rev. 2007, 31 (6), 832–842. 4. A. C. Andreazza, B. N. Frey, B. Erdtmann, M. Salvador, F. Rombaldi, A. Santin, C. A. Gonçalves, F. Kapczinski, Psychiatry Res. 2007, 153, 27–32 5. D. F. McComsey, V. L. Smith-Sw intosky, M. H. Parker, D. E. Brenneman, E. Malatynska, H. S. White, B. D. Klein, K. S. Wilcox, M. E. Milew ski, M. Herb, M. F. A. Finley, Y. Liu, M. L. Lubin, N. Qin, A. B. Reitz, B. E. Maryanof f , J. Med. Chem. 2013, 56, 9019–9030. 6. S. Gupta, P. Masand, B. L. Frank, K. L. Lockw ood, P. L. Keller, J. Clin. Psychiatry 2000, 2 (3), 96–100. 7. S. Hanessian in Iminosugars From synthesis to therapeutic applications (Eds: Philippe Compain and Olivier R. Martin); John Wiley & Sons Ltd: Londres, 1st Ed. 2007. 8. H. Zhang, Y. Ma, X. Sun, Med. Res. Rev. 2010, 30 (2), 270–289. 9. Pinheiro, J. M. A., Preparação de novos pseudo-C-nucleósidos e sua actividade biológica, Doctoral thesis presented in Universidade da Beira Interior, 2006. 10. Baptista, M. G. P., Synthesis of novel potentially bioactive Pseudo-C-Nucleosides for the treatment or control of Bipolar Disorder, Masters’ dissertation presented in Universidade da Beira Interior, 2017.

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N-Methylation of thiazolo[5,4-c]isoquinolines Letícia D. Costa, M. Amparo F. Faustino, Augusto C. Tomé LAQV-Requimte and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. Email: leticia.costa@ua.pt

The synthesis of thiazolo[5,4-c]isoquinolines (3) was first described in 1966 by Taurins and co-workers,1 who also proposed the synthesis of other isomers,2,3 as well as some post-modification reactions.4 Despite the great interest thiazolo[5,4-c]isoquinolines aroused at the time, as far as we know, nothing else was published about the synthesis or application of these compounds. Recently, we found a quick route to synthesize thiazolo[5,4-c]isoquinolines starting from commercially available reagents (Scheme 1). A library of new compounds bearing different substituents were synthesized and the structures of all new compounds were determined by NMR, mass spectrometry and, in some cases, by single crystal X-ray diffraction. Aiming to enhance the solubility of the new thiazolo[5,4-c]isoquinolines in polar solvents, but mainly to modulate their photophysical properties, we performed the Nmethylation of some thiazolo[5,4-c]isoquinolines. In this communication we describe the selective methylation of these compounds in the nitrogen at the 4-position. The chemical and photophysical characterization of these derivatives will be presented and discussed.

Scheme 1. Route for the synthesis and N-methylation of thiazolo[5,4-c]isoquinolines.

Acknowledgements: Thanks are due to Fundação para a Ciência e a Tecnologia (FCT) for the financial support to the project PTDC/QEQ-QOR/6160/2014, the QOPNA research unit (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) through national funds and, when applicable, co-financed by the FEDER within the PT2020 Partnership Agreement. Letícia D. Costa also thanks FCT for her doctoral grant (SFRH/PD/BD/114578/2016). References: 1 C. E. Hall and A. Taurins, Can. J. Chem. 1966, 44, 2473. 2 C. E. Hall and A. Taurins, Can. J. Chem. 1966, 44, 2465. 3 A. Taurins and R. K.-C. Hsia, Can. J. Chem. 1971, 49, 4054.

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Porphyrins and phthalocyanines designed for different applications Sara R. G. Fernandes,a,b Sandra Beirão,a,c Joana Calmeiro,a,d Gabriel Gira,a,e Francisco M. Ferraz,a,e Cláudia C. L. Pereira,e Leandro M. O. Lourenço,d Rosa Fernandes,c Bruno Sarmento,b João P. C. Toméa a

CQE and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Portugal. bINEB and i3S, Universidade do Porto, Porto, Portugal, cCNC.IBILI Consortium, Universidade de Coimbra, Portugal. dLAQVREQUIMTE, Departamento de Química, Universidade de Aveiro, Aveiro, Portugal. eLAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal. Email: jtome@tecnico.ulisboa.pt

Porphyrins and Phthalocyanines are well-known photoactive compounds that have been explored in many different light based technologies.1 In our case, we have been synthesizing several different structures of these dyes in order to tune their physicochemical properties for each of the studied application. For example, to prepare very specific photosensitizers (PSs) for molecular-targeted cancer photodynamic therapy (tPDT) we have mostly been using biological motifs, such as carbohydrates (Fig. 1a) and monoclonal antibodies (Fig. 1b).2 These biomotifs, at their core periphery, allow not just their much better biocompatibility but also their high selectivity to the cancer cells. The obtained biological results against bladder cancer cells have been shown the importance of both strategies, in special when multigalactose units are used in the PSs structures.2 For dye sensitized solar cells (DSSCs) we have been preparing symmetrical and asymmetrical zinc metallated porphyrins based on carboxyphenyl and pyridyl derivatives. Several TiO2-based DSSC devices (Fig. 2) were prepared and their solar energy conversion efficiency determined. The results encourage us to believe that some of our hybrid (nano)materials can be applicable as the photoactive layer in this type of organic solar cells.3 In this communication, some of our recent advances on both applications will be highlighted, presenting some of our most relevant and recent results. Acknowledgements: Support for this work was provided by FCT/MEC to CQE (FCT UID/QUI/0100/2019), INEB (POCI-01-0145-FEDER-007274) and i3S (POCI-01-0145FEDER-007274 and NORTE-01-0145-FEDER-000012), CNC.IBILI (FCT UID/NEU/04539/2019), QOPNA (FCT UID/QUI/00062/2019), LAQV-REQUIMTE (UID/QUI/50006/2019) research units and to the FCT projects (P2020PTDC/QUI-QOR/31770/2017 and P2020-PTDC/QEQ-SUP/5355/2014), through national funds and where applicable cofinanced by the FEDER, within the PT2020 Partnership Agreement. S. F. and S. B. thank FCT for their Ph.D. scholarships (SFRH/BD/129200/2017 and SFRH/BD/140098/2018, respectively) and J. Calmeiro thanks FCT for her research fellow BI/UI51/7955/2019. References: 1.a) L.M.O. Lourenço, D.M.G.C. Rocha, C.I.V. Ramos, M.C. Gomes, A. Almeida, M.A.F. Faustino, F.A.A. Paz, M.G.P.M.S. Neves, A. Cunha, J.P.C. Tomé, ChemPhotoChem, 2019, in press; b) J.M.D. Calmeiro, C.J. Dias, C.I.V. Ramos, A. Almeida, J.P.C. Tomé, M.A.F. Faustino, L.M.O. Lourenço, Dyes and Pygments, 2019, in press. https://doi.org/10.1016/j.dyepig.2019.03.021; c) C. Pereira, Y. Liu, A. Howarth, F. Figueira, J. Rocha, J. T. Hupp, O. K. Farha, J.P.C. Tome, F.A. Almeida Paz, ACS Applied Nano Materials, 2019, 2 (2), 465-469. 2.a) S.R.G. Fernandes, R. Fernandes, B. Sarmento, P.M.R. Pereira, J.P.C. Tomé, Org. Biomol. Chem. 2019, 17, 2579; b) J.T. Ferreira, J. Pina, C. A. F. Ribeiro, R. Fernandes, J.P.C. Tomé, M.S. Rodríguez-Morgade, T. Torres, Chem. Eur. J., 2019, in press. https://doi.org/10.1002/chem.201903546; c) T. F. Ferreira, J. Pina, F. A. C. Ribeiro, R. Fernandes, J. P. C. Tomé, S. M. Rodriguez-Morgade, T. Torres, ChemPhotoChem. 2018, 7, 640-654; d) Korsak B. et al. Int. J. Cancer, 2017, 141 (7), 1478; e) Pereira P. et al. Bioconjug. Chem., 2016, 27 (11), 2762; f) Pereira P. et al. Eur. J. Cancer, 2016, 68, 60. 3.a) S. Mathew, A. Yella, P. Gao, R. Humphry-Baker, F. E. C. Basile, N. Ashari-Astani, I. Tavernelli, U. Rothlisberger, M. K. Nazeeruddin, M. Gratzel, Nat. Chem. 2014, 6, 242–247; b) H. Song, Q. Liu, Y. Xie, Chem. Commun., 2018, 54, 1811— 1824; c) Y. Harima, T. Fujita, Y. Kano, I. Imae, K. Komaguchi, Y. Ooyama, J. Ohshita, J. Phys. Chem. C, 2013, 117, 16364−16370.

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Synthetic approach to di- and trisubstituted porphyrins as templates for donor-π-acceptor derivatives Melani J.A. Reisa, Nuno M.M. Mouraa, Ana M.V.M. Pereirab, M. Graça P.M.S. Nevesa a

LAQV-Requimte and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. bLEPABE, Department of Chemical Engineering, University of Porto – Faculty of Engineering, 4200-465, Porto, Portugal

Email: melani@ua.pt

The potential issues surrounding the use of fossil fuels has been leading to a crescent search for alternative energy sources and it is nowadays a worldwide concern.1 Dye-sensitized solar cells (DSCs) are promising photovoltaic technologies and an alternative to traditional silicon-based solar cells. DSCs present additional advantages due to their transparency, lightness, flexibility and efficient operation when subjected to diffuse radiation. Other desirable features of DSCs are compatibility with low-cost production methods, efficient optical and mechanical properties and high indoor efficiency and power conversion efficiency.2 Porphyrins are a family of heterocyclic compounds that have been attracting much attention by the scientific community due to their potential as catalysts, sensors, electronic devices, therapeutics and theranostic agents, as well as, dyes for solar cells.3 These compounds can be selectively functionalized in the meso and beta-pyrrolic positions, thus allowing the modulation of photochemical and photophysical properties according to the target application.4 Mesodiarylporphyrins are excellent templates to be used for further modifications in the porphyrinic chemistry.5 These derivatives can be prepared by cyclization of the appropriate dipyrromethanes under acidic conditions.6 However, the synthesis of these precursors requires large amounts of pyrrole and their low stability can lead to oxidation during synthesis and isolation processes.5,6 Thus, when the structure is obtained in its oxidized form, an unexpected formation of trisubstituted porphyrin occurs. In this communication, we will present the synthetic pathway to prepare meso-di- and mesotriarylsubstituted porphyrins (Scheme 1) with potential to be used as templates for further modifications to prepare Donor-π-Acceptor porphyrins to be used in future applications as sensitizers in DSCs.

Scheme 1: Synthesis of meso-di- and tri-arylsubstituted porphyrins. Acknowledgements: The authors thank the University of Aveiro and the University of Porto and FCT / MCTES (PIDDAC) for their financial support to the QOPNA Research Unit (UID / QUI / 00062/2019), to the LAQV-REQUIMTE (UIDB/50006/2020) and LEPABE (UID / EQU / 00511/2019) and Portuguese RMN Network. This work was funded by Project FCT POCI-010145-ERDF-030357 - “Taylor-made porphyrinoids for emerging high-efficiency solar energy devices”, funded by the European Regional Development Fund (ERDF) through COMPETE2020 - Operational Program Competitiveness and Internationalization (POCI) and with financial support from FCT / MCTES through national funds (PIDDAC). M.J.A. Reis, N.M.M. Moura (REF.-048-88-ARH / 2018) and A.M.V.M. Pereira thank to FCT and project POCI-01-0145-FEDER-030357 for the research grant and concession agreements. References: 1.M. Ye, X. Wen, M. Weng, J. Iocozzia, N. Zhang, C. Lin, Z. Lin, Mater. Today, 2015, 18, 155. 2.A. Carella, F. Borbone, R. Centore, Front. Chem., 2018, 6, 481. 3.A.F.R. Cerqueira, N.M.M. Moura, V.V. Serra, M.A.F. Faustino, A.C. Tomé, J.A.S. Cavaleiro, M.G.P.M.S. Neves, Molecules, 2017, 22, 1269. 4.K.M. Kadish, K.M. Smith, R. Guilard, Handbook of Porphyrin Science, World Scientific Publishing Company Co: Singapore, 2010, Vol. 1-12. 5.A.J.F.N. Sobral, N.G.C.L. Rebanda, M. da Silva, Lampreia, M.R. Silva, A.M. Beja, J.A. Paixao, A.M.R. Gonsalves, Tetrahedron Lett., 2003, 44, 3971. 6.A Singhal, S. Singh, M.S. Chauhan, Arkivoc, 2016, vi, 144.

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Cationic porphyrin-cyclodextrin derivatives Cláudia P. S. Ribeiroa, João P. C. Toméb, Leandro M. O. Lourençoa a

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. bCQE and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.

Email: claudia.santos.ribeiro7@ua.pt

Cancer photodynamic therapy (PDT) have been used in the treatment of localized tumors.1-5 PDT uses a photosensitizer (PS) agent, appropriate light irradiation and cellular molecular oxygen. When PSs are exposed to the right light in presence of oxygen they can photoreact and produce cytotoxic reactive oxygen species (ROS).1-5 For that, clinical approved PSs, with particular emphasis on photoactive porphyrin (Por) dyes, have been used in different biomedical applications.1,2 Novel neutral and cationic water-soluble Pors peripherally substituted with 4-mercaptopyridine or 4-hydroxypyridine units (1 and 2, respectively) and with cyclodextrin (CD) moieties (3-8) were prepared (Scheme 1). The presence of the CD unit and the multi-positive charges at the Pors periphery core (3a-8a) prevent their aggregation, enhance the solubility in aqueous media and increase the specificity for the target cell‘s receptors. In this communication, it will be reported and discussed the synthesis, structural and spectroscopic characterization of these novel asymmetric porphyrin-cyclodextrin bioconjugates.

Scheme1. Structure of neutral (3-8) and cationic (3a-8a) porphyrin-cyclodextrin bioconjugates. Acknowledgements: Thanks are due to FCT/MCTES for the financial support to QOPNA (FCT UID/QUI/00062/2019), to LAQV-REQUIMTE (UIDB/50006/2020) and CQE (FCT UID/QUI/0100/2019) research units, and FCT projects P2020PTDC/QUI-QOR/31770/2017 and P2020-PTDC/QEQ-SUP/5355/2014, through national founds (PIDDAC) and where applicable co-financed by the FEDER-Operational Thematic Program for Competitiveness and InternationalizationCOMPETE 2020, within the PT2020 Partnership Agreement. C. R. thank FCT for the research fellow BM/UI51/8768/2019. References: 1. P. M. R. Pereira, S. Silva, J. S. Ramalho, C. M. Gomes, H. Girão, J. A. S. Cavaleiro, C. A. F. Ribeiro, J. P. C. Tomé, R. Fernandes, Eur. J. Cancer 2016, 68, 60-69. 2. L. M. O. Lourenço, P. M. R. Pereira, E. Maciel, M. Válega, F. M. J. Domingues, M. R. M. Domingues, M. G. P. M. S. Neves, J. A. S. Cavaleiro, R. Fernandes, J. P. C. Tomé, ChemComm. 2014, 50, 8363. 3. S. A. Thompson, A. Aggarwal, S. Singh, A. P. Adam, J. P. C. Tome, C. M. Drain, Bioorg. Med. Chem., 2018, 26, 5224. 4. a) L. Marciel, L. Teles, B. Moreira, M. Pacheco, L. M. O. Lourenço, M. G. P. M. S. Neves, J. P. C. Tomé, A. F. Faustino, A. Almeida, Future Med. Chem. 2017, 9, 365. 5. J. M. D. Calmeiro, C. J. Dias, C. I. V. Ramos, A. Almeida, J. P. C. Tomé, M. A. F. Faustino, L. M. O. Lourenço, Dyes Pigm.2019, DOI: https://doi.org/10.1016/j.dyepig.2019.03.021.

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Synthesis and luminescence properties of analogues of the green fluorescent protein chromophore Cátia I. C. Esteves,a Inês da Silva Fonseca,a João Rocha,b Artur M. S. Silva,a Samuel Guieua,b a

LAQV-Requimte, Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal. bCICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. Email: catiaiesteves@ua.pt; sguieu@ua.pt

The green fluorescent protein (GFP) from the jellyfish Aequorea victoria is extensively used as a biomarker for fluorescence biological imaging.1 GFP’s chromophore responsible for the fluorescence is the p-hydroxybenzylideneimidazolidinone, and is only fluorescent when confined into the β–barrel of the protein.2 Similarly, synthetic analogues of GFP’s fluorophore are usually non-emissive in solution, due to free rotation around the aryl-alkene bond and (Z/E)-isomerization of the double bond.3 Here we will present the results of the synthesis, characterization and photophysical properties of analogues of the GFP fluorophore (Figure 1). The structure of all synthesized compounds was established by NMR techniques and their photophysical properties by absorption and fluorescence spectroscopy in THF/water mixtures. The introduction of more electron donating substituents induces a red-shift in the absorption and emission. The fluorophores are more emissive in the solid state than in solution, and a study of their crystal structure reveals that the (Z/E)-isomerization is efficiently blocked in the crystals.

Figure 1: Structure of one analogue and emission spectra of solutions with increasing percentage of water. Acknowledgements: Thanks are due to University of Aveiro, FCT/MEC for the financial support to the QOPNA research Unit (FCT UID/QUI/00062/2019), to the LAQV-REQUIMTE (UIDB/50006/2020) and also to the Portuguese NMR Network. This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/ 50011/2019, financed by national funds through the FCT/MCTES. S. Guieu acknowledges the fundings from national funds (OE), through FCT – Fundação para a Ciência e a Tecnologia , I.P., in the scope of the framework contract foreseen in the numbers 4, 5 and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19, and from the Integrated Programme of SR&TD “pAGE – Protein aggregation Across the Lifespan” (reference CENTRO-01-0145-FEDER000003). C.I.C. Esteves acknowledges the 016385-PAC NETDIAMOND project (POCI-01-0145-FEDER016385) for her Post-Doctoral grant (BPD/UI50/7664/2017). References: 1.O.V. Stepanenko, V. V. Verkhusha, I. M. Kuznetsova, V. N. Uversky, K. K. Turoverov, Curr. Protein Pept. Sci. 2009, 9, 338. 2. a) C. L. Walker, K. A. Lukyanov, I. V. Yampolsky, A. S. Mishin, A. S. Bommarius, A. M. Duraj-Thatte, B. Azizi, L.M. Tolbert, K. M. Solntsev, Curr . Opin. Chem. Biol. 2015, 27, 64. b) H. Deng, Z. Zhang, Y. Zhao, C. Yu, L. Gong, D. Yan, X. Zhu, Mater. Today Chem. 2017, 3, 73. 3. a) N. C. Shaner, G. H. Patterson, M. W. Davidson, J. Cell. Sci. 2007, 120, 4247. b) L. M. Tolbert, A. Baldridge, J. Kowalik, K. M. Solntsev, Acc. Chem. Res. 2012, 45, 171.

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Chiral derivatives of xanthones: dual application in medicinal chemistry Ye‛ Zaw Phyo,a,b Joana Teixeira,c Maria Elizabeth Tiritan,b,c,d Sara Cravo,b,c, Andreia Palmeira,b,c Luís Gales,a,e,f Artur M.S. Silva,g Madalena M.M. Pinto,b,c Anake Kijjoa,a,b Carla Fernandesb,c a ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. b Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal. c Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. d CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal. e Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. f i3S – Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, Porto, Portugal. g LAQV-REQUIMTE, Departamento de Química, Universidade de Aveiro, 3810-103 Aveiro, Portugal.

Email: cfernandes@ff.up.pt

Over several years, xanthone derivatives have been the core of a broad number of studies due to their biological and pharmacological activities.1 Recently, chiral derivatives of xanthones (CDXs) have come to arouse great interest considering enantioselectivity associated with biological activities.2,3 From a perspective of Medicinal Chemistry, some CDXs synthetized by our group revealed interesting biological activities.4,5 Besides the potential as new drugs, some CDXs were tested as selectors for chiral stationary phases (CSPs) in liquid chromatography (LC) affording promising enantioresolution results.6 Based on the most promising CDXs, twelve new enantiomerically pure analogues were synthetized for biological activity evaluation as well as selectors for new CSPs.7 The CDXs comprising one, two, three or four chiral moieties were covalently bonded to a chromatographic support, and further packed into LC stainless-steel columns. Good enantioseparation for some chiral analytes was observed in the evaluation of the new CSPs. In addition, assessment of chiral recognition mechanisms was performed by computational studies using molecular docking approach. X-Ray analysis was used to establish the 3-D structure of one CDX. The evaluation of the growth inhibitory activity of the new CDXs, in three human tumor cell lines, is ongoing. This work allowed the development of new chromatographic tools with a broad variety of applications in Medicinal Chemistry, including evaluation of enantiomeric purity of drugs and bioactive compounds, pharmacokinetic studies, analysis of the stereochemistry of natural compounds, monitoring enantiomeric reactions and preparative enantioresolution. Additionally, the new synthetized CDXs may also be a source of new bioactive agents. Acknowledgements: This work was supported by the Strategic Funding UID/Multi/04423/2019 through national funds provided by FCT and ERDF, through the COMPETE –POFC program in the framework of the program PT2020; the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790 and 3599-PPCDT), co-financed by COMPETE 2020, under the PORTUGAL 2020 Partnership Agreement, through the ERDF, CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019, QOPNA research project (FCT UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020), and Portuguese NMR network. References: 1. A.I. Shagufta, Eur. J. Med. Chem., 2016, 116, 267. 2. C. Fernandes, M.L. Carraro, J. Ribeiro, J. Araújo, M.E. Tiritan, M.M.M. Pinto, Molecules, 2019, 24(4), 791. 3. J. Araújo, C. Fernandes, M. Pinto, M.E. Tiritan, Molecules, 2019, 24(2), 314. 4. C. Fernandes, K. Masawang, M.E. Tiritan, E. Sousa, V. Lima, C. Afonso, H. Bousbaa, W. Sudprasert, M. Pedro, M. Pinto, Bioorg. Med. Chem. 2014, 22, 1049. 5. C. Fernandes, A. Palmeira, I.I. Ramos, C. Carneiro, C. Afonso, M.E. Tiritan, H. Cidade, P.C.A.G. Pinto, M.L.M.F.S. Saraiva, S. Reis, M.M.M. Pinto, Pharmaceuticals, 2017, 10, 50. 6. C. Fernandes, M.E. Tiritan, S, Cravo, Y. Phyo, A. Kijjoa, A.M.S. Silva, Q.B. Cass, M.M.M. Pinto, Chirality, 2017, 29(8),430-442. 7. Y.Z. Phyo, J. Teixeira, M.E. Tiritan, S. Cravo, A. Palmeira, L. Gales, A.M.S Silva, A. Kijjoa, M.M.M Pinto, C. Fernandes, Chirality, 2019, 1.

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Meso-substituted corroles from nitrosoalkenes and dipyrromethanes Susana M. M. Lopes, Teresa M. V. D. Pinho e Melo CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal. Email: smlopes@uc.pt

Corroles are a class of contracted porphyrinoids with a direct pyrrole-pyrrole link, trianionic character as ligand and high electron density. The structural, spectroscopic and photophysical properties of free base corroles and their metal complexes make them ideal compounds for numerous applications,1 namely in photodynamic therapy.2 The most common methods to prepare corroles involve the synthesis of bilanes by acid-catalyzed condensation of pyrrole derivatives with aldehydes followed by oxidation.3 In the last decade, our research group has been interested in the reactivity of nitrosoalkenes and azoalkenes which has been applied in the functionalization and synthesis of heterocycles.4 In this context, a new route to dipyrromethanes has been developed. The dehydrohalogetion of α,α-dihalo-oximes and α,α-dihalo-hydrazones in the presence of pyrrole afforded dipyrromethanes 2, via two consecutive hetero-Diels-Alder reactions or conjugated additions of the in situ generated nitrosoalkenes and azoalkenes (Scheme 1a).5 Thus, we envisaged that the replacement of pyrrole by dipyrromethane would lead to an approach to tetrapyrrolic compounds. Herein, we describe a novel approach to trans-A2B-corroles based on the reactivity of nitrosoalkenes towards dipyrromethanes. The synthetic strategy involves the synthesis of bilanes from α,α-dihalo-oximes and dipyrromethanes followed by oxidative macrocyclization to afford a new class of tetrapyrrolic macrocycles (Scheme 1b).

Scheme 1: a) Synthesis of dipyrromethanes. b) Synthesis of bilanes and corroles.

Acknowledgements: Coimbra Chemistry Centre (CQC) supported by the Portuguese Agency for Scientific Research, “Fundação para a Ciência e a Tecnologia” (FCT) through project UID/QUI/00313/2019. We also acknowledge the UC-NMR facility for obtaining the NMR data (www.nmrccc.uc.pt). References: 1. (a) Ghosh, A. Chem. Rev. 2017, 117, 3798-3881. (b) Nardis, S.; Mandoj, F.; Stefanelli, M.; Paolesse, R. Coord. Chem. Rev. 2019, 388, 360-405. (c) Barata, J. F. B.; Neves, M. G. P. M. S.; Faustino, M. A. F.; Tomé, A. C.; Cavaleiro, J. A. S. Chem. Rev. 2017, 117, 3192-3253. 2. Teo, R. D.; Hwang, J. Y.; Termini, J.; Gross, Z.; Gray, H. B. Chem. Rev. 2017, 117, 2711-2729. 3. Orłowski, R.; Gryko, D.; Gryko, D. T. Chem. Rev. 2017, 117, 3102-3137. 4. Lopes, S. M. M.; Cardoso, A. L.; Lemos, A.; Pinho e Melo, T. M. V. D. Chem. Rev. 2018, 118, 1132411352. 5. Pereira, N. A. M.; Lopes, S. M. M.; Lemos, A.; Pinho e Melo, T. M. V. D. Synlett 2014, 25, 423-427.

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Synthesis of new N-substituted diketopyrrolopyrroles Vítor A. S. Almodôvar, Liwia Jankowska, Augusto C. Tomé LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal Email: v.almodovar@ua.pt

Diketopyrrolopyrroles (DPP) represent a class of brilliant red and strongly fluorescent high-performance pigments that have exceptional light, heat and environmental stability.1 Diketopyrrolopyrrole molecules have several centers of reactivity which allow their transformation into diversely functionalized derivatives with increased performance in a range of different applications.2–5 The synthesis of N,N’-bis(pentafluorobenzyl)diketopyrrolopyrrole derivatives (compounds similar to 2 but with different Ar groups) has been reported recently.6 Considering that pentafluorophenyl groups give nucleophilic aromatic substitutions with a range of nucleophiles, we decided to synthesize the N,N’-bis(pentafluorobenzyl)-diketopyrrolopyrrole 2 and to study its reaction with thiols and phenols (Scheme 1). The results of that work, including the structural characterization of the new compounds 2 and 3, will be presented and discussed in this communication.

Scheme 1: Synthetic route to the new N-substituted diketopyrrolopyrroles. Acknowledgements: Thanks are due to the University of Aveiro and FCT for the financial support to project PTDC/QEQ-QOR/6160/2014, the QOPNA research Unit (FCT UID/QUI/00062/2019) and the LAQVREQUIMTE (UIDB/50006/2020) through national funds and, where applicable, co-financed by FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. Vítor A.S. Almodôvar thanks FCT for his doctoral grant (SFRH/BD/135598/2018). References: 1. M. Grzybowski, D. T. Gryko, Adv. Optical Mater. 2015, 3, 280. 2. A. Tang, C. Zhan, J. Yao, E. Zhou, Adv. Mater. 2017, 29, 1600013. 3. M. Kaur, D. H. Choi, Chem. Soc. Rev. 2015, 44, 58. 4. Y. Cai, P. Liang, Q. Tang, X. Yang, W. Si, W. Huang, Q. Zhang, X. Dong, ACS Nano 2017, 11, 1054. 5. A. Chiminazzo, G. Borsato, A. Favero, C. Fabbro, C. E. McKenna, L. G. D. Carbonare, M. T. Valenti, F. Fabris, A. Scarso, Chem. Eur. J. 2019, 25, 3617. 6. a) J. Calvo-Castro, G. Morris, A. R. Kennedy, C. J. McHugh, Cryst. Growth Des. 2016, 16, 2371. b) J. Calvo-Castro, G. Morris, A. R. Kennedy, C. J. McHugh, Cryst. Growth Des. 2016, 16, 5385.

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Synthesis of novel tetraoxodipyrroloporphyrins Ana F. R. Cerqueira, Milena Bors, Augusto C. Tomé LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal Email: anacerqueira@ua.pt

Porphyrin derivatives, due to their photophysical properties, are particular interesting for a diversity of applications, namely in catalysis, sensors, solar cells, photodynamic therapy or photodynamic inactivation of pathogenic microorganisms.1 Our research group has been particularly interested on the development of new methods to functionalize meso-tetraarylporphyrins, mainly at the β-pyrrolic positions.2 In this context, we have reported the synthesis of pyrroloporphyrins3 and their photooxidation to 1,3-dioxopyrroloporphyrins.4 In this communication, we report the transformation of two isomeric dipyrroloporphyrins into the corresponding tetraoxodipyrroloporphyrins 1 and 2 (Figure 1). The synthesis and the structural characterization of the new compounds will be discussed.

Figure 1 – Tetraoxodipyrroloporphyrins synthesized.

Acknowledgements: Thanks are due to the University of Aveiro and FCT for the financial support to project PTDC/QEQ-QOR/6160/2014, the QOPNA research Unit (FCT UID/QUI/00062/2019) and the LAQVREQUIMTE (UIDB/50006/2020) through national funds and, where applicable, co-financed by FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. Ana F. R. Cerqueira thanks FCT for her doctoral grant (SFRH/BD/135597/2018). References: 1. Handbook of Porphyrin Science; Kadish, K. M.; Smith, K. M.; Guilard, R., Eds.; World Scientific: Singapura, 2010–2016; Vol. 1–44. 2. A. F. R. Cerqueira, N. M. M. Moura, V. V. Serra, M. A. F. Faustino, A. C. Tomé, J. A. S. Cavaleiro, M. G. P. M. S Neves, Molecules 2017, 22, 1269. 3. A. M. G. Silva, M. A. F. Faustino, A. C. Tomé, M. G. P. M. S. Neves, A. M. S. Silva, J. A. S. Cavaleiro, J. Chem. Soc., Perkin Trans. 1 2001, 2752. 4. C. M. B. Carvalho, M. G. P. M. S. Neves, A. C. Tomé, F. A. A. Paz, A. M. S. Silva, J. A. S. Cavaleiro, Org. Lett. 2011, 13, 130.

165

Synthesis PC86

Towards new BACE1 inhibitors: in silico studies and synthesis M. Maia,a A. Palmeira,a D. Resende,a,b L. Gales,c L. Kiss,d E. Sousaa,b a

Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University

of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; bInterdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; cICBAS-Instituto de Ciências Biomédicas Abel Salazar, & I3S, Universidade do Porto, Portugal; dBIAL – Portela & Cª, S.A., À Avenida da Siderurgia Nacional, 4745-457 Coronado (S. Romão e S. Mamede), Portugal

Email: esousa@ff.up.pt

Beta-site APP-cleaving enzyme (BACE)1 is a type-1 membrane-anchored aspartyl protease playing an essential role in the release of Aβ peptides and Alzheimer’s Disease (AD) progression. Hence, the development of potent BACE1 inhibitors represents a logical approach for AD therapy development and it have been widely explored by the pharmaceutical industry worldwide.1 Herein, we report the design of a virtual library of 300 compounds and the synthesis of a first set of derivatives for in vitro BACE1 inhibition assessment. These compounds arise from the conjugation of several fragments with aliphatic and aromatic amines, motifs identified in the literature by their ability to establish essential interactions with the amino acids present in the catalytic pocket of BACE1. Affinity for BACE1 was measure through the binding energy estimation of the ligand-protein complex. Additionally, the compounds designed were assessed through the Lipinski’s rule of 5 and additional attributes crucial for central nervous system (CNS) drugs were also considered.2 A first series of compounds which arises from the conjugation of xanthydrol with several sulfamides was obtained according with the conditions stated in Figure 1. Structural elucidation was performed through 1H and 13C NMR and X-ray crystallographic techniques.

Figure 1. Reactional scheme for the synthesis of xanthydrol-sulfamide conjugates.3

As a future work, biological activity for BACE1 inhibition will be assessed through in vitro cell-free and cell-based screening assays. Acknowledgements: We thank the UID/Multi/04423/2019 through national funds provided by FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the program PT2020. This research was developed under Project No. POCI-01-0145-FEDER-028736, cofinanced by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds. Miguel Maia acknowledges his FCT grant (SFRH/BD/146211/2019). References: 1. Maia MA, Sousa E. BACE-1 and γ -Secretase as Therapeutic Targets for Alzheimer’ s Disease. Pharmaceuticals. 2019;12(41). doi:10.3390/ph12010041 2. Pajouhesh H, Lenz GR. Medicinal Chemical Properties of Successful Central Nervous System Drugs. Neurotherapeutics. 2005;2:541-553. doi: https://doi.org/10.1602/neurorx.2.4.541 3. Moskalyk RE, Chatten LG. Alkylation by secondary alcohols. I. The reaction of xanthydrol with some N1monosubstituted sulfanilamides and related compounds. Canadian Journal of Chemistry. 1967;45(13):14111424. doi.org/10.1139/v67-233

166

Synthesis PC87

Synthesis of new proteomimetic quinazolinone alkaloids modified at the anthranilic and tryptophan moiety W. Udomsak,a D. Resende,a,b A. Kijjoa,b,c A. M. S. Silva,d M. Pinto,a,b E. Sousaa,b* Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. b ICBAS- Abel Salazar Institute of Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal. cCIIMAR Interdisciplinary Centre of Marine and Environmental Research, 4150-171 Matosinhos, Portugal. dOrganic Chemistry Group, LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal. a

Email: esousa@ff.up.pt

For a long time, antimicrobial agents have been used to treat infectious diseases. However, nowadays, the therapeutic effect of antimicrobial agents is dramatically decreasing due to their misuse. This can stimulate microorganisms to develop resistance, creating one of the world's most urgent public health problems.1 Over the last years, marine natural products (MNPs) have been an inspiration to the development of new lead compounds, due to their broad spectrum of biological activities. Particularly indolylmethyl pyrazinoquinazoline alkaloids, containing an indolomethyl pyrazino[1,2-b]quinazoline-3,6dione scaffold as the core structure, have attracted our attention due to their promising biological activities, including neofiscalin A that exhibited potent antibacterial activity against Staphylococcus aureus and Enterococcus faecalis (MIC = 8 µg/mL).2 Herein we report the synthesis of indolomethyl pyrazino[1,2-b]quinazoline-3,6-dione derivatives by a three-component one-pot methodology using different chiral N-L-Bocprotected α-amino acids, tryptophan methyl esters, and anthranilic acids (Scheme 1).3 The syntheses include modifications in the anthranilic acid and tryptophan moieties in order to improve their antimicrobial activity.

Scheme 1 One-Pot Synthesis of indolomethyl pyrazino[1,2-b] quinazoline-3,6-dione scaffold.

Synthetic details as well as structure characterization (by 1D and 2D NMR studies) of the new synthesized compounds will be presented and discussed. Acknowledgements: Support for this work was provided by the Strategic Funding UID/Multi/04423/2019 and under the project QOPNA (UID/QUI/00062/2019); LAQV-REQUIMTE (UIDB/50006/2020); PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds, Udomsak W. thanks partial scholarship from Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand, to international internship at Faculty of Pharmacy, Porto University. References: 1. https://www.who.int/antimicrobial-resistance/global-action-plan/en/ (accessed 15/11/2019). 2. Bessa, L. J.; Buttachon, S.; Dethoup, T.; Martins, R.; Vasconcelos, V.; Kijjoa, A.; da Costa, P. M. Neofiscalin A and Fiscalin C Are Potential Novel Indole Alkaloid Alternatives for the Treatment of Multidrugresistant Gram-Positive Bacterial Infections. FEMS Microbiol. Lett. 2016, 363 (15), 5–9. https://doi.org/10.1093/femsle/fnw150. 3. Liu, J. F.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. Three-Component One-Pot Total Syntheses of Glyantrypine, Fumiquinazoline F, and Fiscalin B Promoted by Microwave Irradiation. J. Org. Chem. 2005, 70 (16), 6339–6345. https://doi.org/10.1021/jo0508043.

167

Synthesis PC88

Targeting MAO inhibition with novel N-propargylated chromanone derivatives Amina Moutayakine,a,b,e Mariam Dubiel,f Holger Stark,f Stefano Alcaro,c,d Donatella Bagetta,c,d José M. Padrón,e Anthony J. Burkea,b aDepartment

of Chemistry, University of Évora, School of Science and Technology, Rua Romão Ramalho, 59, 7000 Évora, Portugal. de Química de Évora-Requimte-LAQV, University of Évora, Institute for Research and Advanced Training (IIFA), Rua Romão Ramalho,59,7000 Evora, Portugal. cNet4Science Academic Spin-Off, University "Magna Græcia" of Catanzaro, Campus Universitario "S.Venuta", Catanzaro, Italy. dDepartment of "Scienze della Salute", University "Magna Græcia" of Catanzaro, Campus Universitario "S. Venuta", Catanzaro, Italy. eBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Spain. fHeinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr, 1, 40225 Duesseldorf, Germany. bCentro

Email: amina.moutayakine@gmail.com

Chromanone are without any doubt an important family of pharmacophores and privileged structures in medicinal chemistry.Recently our group, developped a new methodology involving Pd catalyzed cyclizations of ortho-bromoarylaldehydes to access libraries of both Chromanones and Chromanols (Scheme 1).1 Due to our interest in developing new Monoamine Oxidase (MAO) inhibitors we are currently interested in targeting a family of unique propargylamine substituted chromanes the strategy for which is shown in Scheme 1. Previous molecular modelling studies has shown that compound (4) (Scheme 1 R = H) should bind well with MAO-B. Using known methods, which included sustainable reductive aminations, we could successfully access the target compounds (4).2,3 These compounds were screened against both MAOA and MAOB, as well as in the SH-SY5Y brain tumor cell line, which is a good model for accessing compound cytotoxicity.

Scheme 1 Preparation of 4-aminochromanones (4) using reductive amination as a key step.

Acknowledgements: We thank the Fundação para a Ciência e Tecnolgia for financial support to CQE through grant Pest-OE/QUI/UI0619/2019. We acknowledge COST action 15135, Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig). References: 1 H. Viana, C. S. Marques, C. A. Correia, K. Gilmore, L. Galvão, L.Vieira, P. H. Seeberge, A.J. Burke, ChemistrySelect 2018, 3, 1-7. 2 B. Miriyala, S. Bhattacharyyab, J.S. Williamsona, Tetrahedron 60, 2004, 1463–1471 3 E.M Dangerfield, C. H Plunkett, A.L Win-Masson, B.L Strocker, M. S Timmer, J. Org Chem, 2010, 75, 54705477.

168

Synthesis PC89

Synthesis of drug metabolites of abuse of Benzo Fury´s Inês Fino, Catarina Cardoso, Luísa M. Ferreira, Paula S. Branco LAQV-Requimte and Department of Chemistry, University of Aveiro, 3010-193 Aveiro, Portugal Email: paula.branco@fct.unl.pt

Benzofurans, also known by users as "Benzo Fury´s" are synthetic phenethylamines, a growing group of designer drugs belong to the so-called novel psychoactive substances (NPS). Benzofurans act preferentially by disturbing the functioning of serotonergic circuits being a serotonin–norepinephrine–dopamine reuptake inhibitor. Benzofurans induces entactogenic and stimulant effects and is the reason behind the considerable number of recent benzo fury-related deaths. Some recent research work put in evidence that the toxicity of benzo fury is now beginning to emerge revealing an alarming public health threat regarding the abuse of these NPS. The first benzofurans appearing on the drug scene in 2010-11, were 5-(2-aminopropyl) benzofuran (5-APB) and 6-(2-aminopropyl) benzofuran (6-APB). These compounds had been previously patented in 2006 as potential therapeutic drugs for eating disorders and seizures, due to their action as serotonergic agonists.1 Here we present our efforts towards the synthesis of standards for toxicological studies. The synthesis and of 5-APB and 6-APB metabolites namely the oxidized metabolites (1-4) are being addressed using as starting material the salicylic acid derivatives, 4-bromo-2-methoxybenzoic acid and 2-methoxybenzoic acid. (Figure 1).

Figure 1: Benzo Fury´s drugs and their oxidized metabolite 1-4.

Acknowledgements: We thank the Associate Laboratory for Green Chemistry- LAQV which is financed by national funds from FCT/MCTES (UID/QUI/50006/2019. The National NMR Facility supported by Fundação para a Ciência e Tecnologia (RECI/BBB-BQB/0230/2012). We acknowledge the Laboratório de Análises REQUIMTE for the technical support for the mass spectrometry analyses. References: 1. a) Rita Roque Bravo et al., Benzo fury: A new trend in the drug misuse scene, J Appl Toxicol. (2019)1-13. b) Anna Rickli et al., “Pharmacological Profile of Novel Psychoactive Benzofurans,” British Journal of Pharmacology 172, no. 13 (2015) 3412–25.

169

Synthesis PC90

Synthesis and anticancer activity of triazole-benzimidazolechalcone hybrids Liza Sahera,b, Amar Djemouic,d,e, Abdelkader Naouric,e,f, Mohammed Ridha Ouahranic, Djamila Djemouid, Souli Lahcenee, Mokhtar Boualem Lahreche, Leila Boukennaf, Hélio M. T. Albuquerquea, Djenisa H. A. Rochaa,g, Fátima Liliana Monteirob, Luísa A. Helguerob, Khaldoun Bacharif, Oualid Talhia,f, Artur M. S. Silvaa a

LAQV-REQUIMTE, Department of Chemistry University of Aveiro, 3810-193, Aveiro, Portugal. bInstitute of Biomedicine (iBiMED), Department of Medical Sciences University of Aveiro, 3810-193, Aveiro, Portugal. cDepartment of Chemistry, Faculty of Exact Sciences and Informatics ZIANE Achour University, Djelfa, Algeria. dDepartment of Chemistry, Faculty of Exact Sciences Echahid Hamma Lakhdar University of El Oued, Algeria. eLaboratory of Organic Chemistry and Natural Substance Faculty of Exact Sciences and Informatics, ZIANE Achour University, Djelfa, Algeria. fCentre de Recherche Scientifi que et Technique en Analyses Physico-Chimiques CRAPC, BP384, Bou-Ismail, 42004, Tipaza, Algeria. gCICECOAveiro Institute of Material University of Aveiro, 3810-193, Aveiro, Portugal

Email: liza.saher@ua.pt

Novel series of triazole-benzimidazole-chalcone hybrid compounds have been synthesized via click chemistry, between different azide derivatives and substituted benzimidazole terminal alkynes bearing a chalcone moiety. The starting alkynes are prepared via base-catalysed nitrogen alkylation of presynthetized benzimidazole-chalcone substrates (Scheme 1). All the intermediates as well as the final products are fully characterized by 1D and 2D NMR and mass spectrometry techniques. HMBC correlations permits the identification of a unique 1,4-disubstitued triazole-benzimidazole-chalcone isomer. Evaluation of the anti-proliferative potential in breast and prostate cancer cell lines showed that the presence of chloro substituents at the chalcone ring of the triazole-benzimidazole-chalcone skeleton enhanced the cytotoxic effects. The benzyl group linked to the 1,2,3-triazole moiety provides more antiproliferative potential.1

Scheme 1. Synthetic route for the preparation of benzimidazole-chalcone intermediates 7a-h and triazolebenzimidazole-chalcone hybrids 10a-h and 11a-f. Acknowledgements: Thanks are due to University of Aveiro and FCT/MEC for the financial support to the QOPNA research project (FCT UID/QUI/00062/2013), LAQV-REQUIMTE (UIDB/50006/2020) and to the CICECO-Aveiro Institute of Materials(POCI-01-0145-FEDER-007679; FCT UID/CTM/50011/2013), financed by tional funds and when appropriate cofinanced by FEDER under the PT2020 Partnership Agreement, and to the Portuguese NMR Network.We would like also to thank FCT/MEC and the General Directorate for Scientific Research and Technological Development – DGRSDT of Algeria and Agence Thématique de Recherche en Sciences et Technologie ATRST for approving the co-financed bilateral project PT-DZ/0005. We further wish to thank Pr. Farid Messelmi the Dean of Faculty of Exact Sciences and informatics in the University of Djelfa for providing necessary laboratory facilities to carry out the research work smoothly. The biological assays were carried out at iBiMED's cell culture facility which is supported by national funds through FCT project UID/BIM/04501/2019. References: 1. A. Djemoui, A. Naouri, M. R. Ouahrani, D. Djemoui, S. Lahcene, M. B. Lahrech, L. Boukenna, H. M.T. Albuquerque, L. Saher, D. H.A. Rocha, F. L. Monteiro, L. A. Helguero, K. Bachari, Oualid Talhi, A. M.S. Silva, J. Mol. Struct, 2019, 127487.

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AUTHOR INDEX

Author index

Abrunhosa, A. J. ..............................................................................................................61 Afonso, C. A. M. .......................................................................................... 32, 72, 88, 105 Afonso, C. M. M. ..............................................................................................................75 Afonso, J. ........................................................................................................................99 Albuquerque, H. M. T............................................................................................. 140, 170 Alcaro, S. .......................................................................................................................168 Alho, D. P. S. .................................................................................................................142 Alma, P. N. ......................................................................................................................36 Almeida Paz, F. A. ........................................................................................... 44, 112, 128 Almeida, A. ......................................................................................................................70 Almeida, J......................................................................................................................154 Almeida, J. R. .......................................................................................................... 43, 134 Almeida, M............................................................................................................... 53, 155 Almeida, P. ......................................................................................................................40 Almodôvar, V. A. S. ............................................................................................... 124, 164 Alves, A. J. S. ........................................................................................................ 137, 139 Alves, C. C.......................................................................................................................71 Alves, M. A. ...................................................................................................................114 Alves, M. Q. ...................................................................................................................155 Alves, N. G. ............................................................................................................. 52, 139 Alves, P. C. .................................................................................................... 135, 143, 144 Alves, S. ..........................................................................................................................87 Ambrósio, F. ..................................................................................................................113 Andrade, K.......................................................................................................................72 André, V. ....................................................................................................... 135, 143, 144 António, J. P. M. ............................................................................................................125 Antunes, A. M. M. ..........................................................................................................143 Araújo, A. N. ............................................................................................................ 66, 106 Araújo, M. E. M. ...............................................................................................................93 Araújo, M. J. ....................................................................................................................60 Araújo, R. L....................................................................................................................149 Arnaut, L. G. ..................................................................................................................126 Aroso, R. T. ...................................................................................................................126 Ascenso, J. R. ...............................................................................................................116 Azevedo, C. M. G. ...........................................................................................................75 Baby, A. R. ......................................................................................................................93 Bachari, K. .....................................................................................................................170 Bagetta, D......................................................................................................................168 Bagnato, V. S. ...............................................................................................................126 Baleizão, C. .....................................................................................................................94 Baptista, S. J. ..................................................................................................................86 Barata, J. F. B.......................................................................................................... 97, 152 Barbosa, C. M................................................................................................................101 Barbosa, F. ....................................................................................................................138 Barrulas, P. C. .................................................................................................................71 Barrulas, R. V. .................................................................................................................98 Bártolo, I. ............................................................................................................... 137, 139 Batista, V. F. ....................................................................................................................81 Beirão, S................................................................................................................ 130, 158 Berberan-Santos, M. N. .................................................................................................116 Bernardo, M. ....................................................................................................................94 Beutler, J. A. ..................................................................................................................141 Boas, C. V. ......................................................................................................................43

173

Author index Bonifácio, V. D. B.............................................................................................................90 Bordado, J. C.................................................................................................................110 Borges, F. ........................................................................................................................31 Bors, M. .........................................................................................................................165 Botelho, M. F. .......................................................................................................... 74, 145 Bouissane, L. .................................................................................................................153 Boukenna, L. .................................................................................................................170 Bousbaa, H. ...................................................................................................................127 Braga, S. S. ................................................................................................... 112, 123, 155 Branco, L. C............................................................................................................. 76, 147 Branco, P. S. .................................................................................................................169 Brandão, P.....................................................................................................................145 Brás, A. R. .......................................................................................................................64 Bravo, C. ....................................................................................................... 135, 143, 144 Brites, G. .........................................................................................................................74 Brito, A. F.........................................................................................................................74 Brito, R. M. M............................................................................................................. 52, 84 Bryant, S. D. ....................................................................................................................58 Burke, A. J. .................................................................................. 59, 67, 71, 102, 145, 168 Caetano, J. A. T...............................................................................................................69 Calado, P.......................................................................................................................119 Calmeiro, J. M. D. ...................................................................................... 70, 77, 129, 158 Calvete, M. J. F. .............................................................................................. 55, 100, 126 Camões, F. ....................................................................................................................155 Campos, A. ......................................................................................................................43 Campos, M. .....................................................................................................................74 Campos-Gonçalves, I. ...................................................................................................102 Caparica, R......................................................................................................................93 Cardoso, A. L...................................................................................................................71 Cardoso, C. ...................................................................................................................169 Cardoso, I. C. S. ..............................................................................................................79 Cardoso, S. M.................................................................................................. 44, 123, 128 Carreira, C. A...................................................................................................................69 Carreiro, E. P. .......................................................................................................... 67, 102 Carrilho, R. M. B. .............................................................................................................82 Carvalhal, F. ....................................................................................................................43 Carvalho, C....................................................................................................................133 Cascante, M. .................................................................................................................142 Casimiro, T. .....................................................................................................................90 Cavaca, L. A. S..............................................................................................................105 Cavaleiro, J.............................................................................................................. 97, 153 Cerqueira, A. F. R. .........................................................................................................165 Chame, C. .......................................................................................................................53 Cidade, H. .....................................................................................................................134 Coelho, C. T. P. .............................................................................................................109 Coelho, J. A. S................................................................................................... 72, 88, 105 Coelho, P.........................................................................................................................49 Coimbra, J. R. M. .............................................................................................................86 Conde, J. .........................................................................................................................34 Connelly, J. ......................................................................................................................92 Correia, C. M. ..................................................................................................................78 Correia-da-Silva, M. ......................................................................................... 43, 133, 134 Côrte-Real, L. ..................................................................................................................64 Corvo, L. ..........................................................................................................................89 Corvo, M. C. ....................................................................................................................98 Costa, C. C. ...................................................................................................................155

174

Author index Costa, J. G.......................................................................................................................93 Costa, L. D.....................................................................................................................157 Costa, M. .......................................................................................................................102 Costa, P.........................................................................................................................138 Costa, S. P. G..................................................................................................................39 Craveiro, A. C. ...............................................................................................................102 Cravo, S. .......................................................................................................................162 Cristelo, R......................................................................................................................133 Cristiano, M. L. S. ..........................................................................................................103 Cruz, B. A. S. .................................................................................................................127 Cruz, L. ............................................................................................................................41 Cunha, S. ........................................................................................................................75 da Silva Fonseca, I. .......................................................................................................161 da Silva, G. J. ................................................................................................................126 da Silva, L......................................................................................................................108 Dabrowski, J. M. ............................................................................................................126 Damas, L. ........................................................................................................................82 Daniel-da-Silva, A. L. .......................................................................................................97 Darvishi, E. ....................................................................................................................141 de Araújo, L. G. .............................................................................................................109 Dias, C...........................................................................................................................119 Dias, C. J. ...................................................................................................... 120, 148, 151 Dias, L.D..........................................................................................................................82 Dias, R. A. .....................................................................................................................155 Dinis, T. C. P. ..................................................................................................................86 Diogo, H. P. ............................................................................................................. 96, 117 Djemoui, A. ....................................................................................................................170 Djemoui, D. ....................................................................................................................170 Duarte, A. R. ....................................................................................................................76 Duarte, B. ......................................................................................................................133 Duarte, M. T...................................................................................................................143 Dubiel, M. ......................................................................................................................168 Durães, F.......................................................................................................................138 Eddahmi, M. ..................................................................................................................153 Esteves, C. I. C..............................................................................................................161 Eusébio, M. E. S. .............................................................................................................55 Fagundes, N. ...................................................................................................................60 Fardilha, M.....................................................................................................................122 Faustino, H. ............................................................................................................. 63, 125 Faustino, M. A. F. ..................................................... 70, 120, 122, 148, 149, 151, 153, 157 Favero, Y. ......................................................................................................................108 Fernandes, A. C...............................................................................................................69 Fernandes, A. S...............................................................................................................93 Fernandes, C. ................................................................................................................162 Fernandes, E. .................................................................66, 78, 87, 89, 104, 106, 107, 132 Fernandes, P. A.............................................................................................................107 Fernandes, R. ................................................................................................ 129, 130, 158 Fernandes, S. R. G. ............................................................................................... 131, 158 Ferraz, F. M. ..................................................................................................................158 Ferraz, R. .................................................................................................................. 60, 68 Ferreira de Oliveira, J. M. P. ............................................................................................87 Ferreira, J. P. S. ...................................................................................................... 44, 128 Ferreira, J. R. M.............................................................................................................150 Ferreira, L. M. .......................................................................................................... 99, 169 Figueiredo, J. A. ............................................................................................................156 Filho, C. .........................................................................................................................102

175

Author index Fino, I. ...........................................................................................................................169 Firmino, A. D. G. ..............................................................................................................94 Fonte, M. .........................................................................................................................60 Fonte, P. ..........................................................................................................................93 Fontes, L. ........................................................................................................................95 Fontinha, D. ............................................................................................................. 68, 139 Francisco, A.....................................................................................................................53 Francisco, T. ..................................................................................................................140 Franco, A. R. .................................................................................................................134 Franco, B. ......................................................................................................................147 Freitas, M..................................................................................... 66, 78, 89, 104, 106, 107 Freitas, V. ........................................................................................................................41 Freitas-Silva, J. ..............................................................................................................138 Gago, S. ..........................................................................................................................76 Gales, L. ................................................................................................................ 162, 166 Galhano dos Santos, R..................................................................................................110 Gamelas, S. R. D. ...................................................................................................... 70, 77 Garcia, M. H. ...................................................................................................................64 Garcia, S. N. ....................................................................................................................85 Geraldes, C. F. G. C. .......................................................................................................61 Gira, G. ..........................................................................................................................158 Góis, P. M. P. .......................................................................................................... 63, 125 Gomes, A.........................................................................................................................60 Gomes, A. T. P. C............................................................................................................70 Gomes, C. ............................................................................................................... 91, 113 Gomes, D. M. P. ..............................................................................................................61 Gomes, J. ........................................................................................................................68 Gomes, M. .....................................................................................................................156 Gomes, P................................................................................................................... 60, 68 Gomes, P. M. O. ..............................................................................................................44 Gomes, R. F. A. ................................................................................................. 72, 88, 105 Gomes, V.........................................................................................................................41 Gonçalves, C. ................................................................................................................134 Gonçalves, G. ................................................................................................................120 Gonçalves-Pereira, R. .....................................................................................................56 Gonzalez, A. C. S. ...........................................................................................................82 Goulart, M......................................................................................................................104 Gouverneur, V. ................................................................................................................27 Grosso, C. .......................................................................................................................71 Guedes, R. ......................................................................................................................40 Guedes, R. C. ............................................................................................................ 58, 85 Guerreiro Alves, N. ........................................................................................................137 Guieu, S. ................................................................................... 51, 95, 115, 150, 155, 161 Gul, S. .............................................................................................................................58 Gustafson, K. R. ............................................................................................................141 Helguero, L. A........................................................................................................ 120, 170 Herranz, M. Á. ...............................................................................................................120 Hummeid, S. ....................................................................................................................40 Isca, V. M. S. ............................................................................................................. 69, 72 Ismael, M. I. ...................................................................................................................156 Janela, J. .......................................................................................................................132 Jankowska, L. ................................................................................................................164 Joaquinito, A. S. ............................................................................................................148 Jorda, R. ..........................................................................................................................56 Jorge, A. M. .....................................................................................................................87 Júlio, A.............................................................................................................................93

176

Author index Justino, G. C. ................................................................................................... 62, 113, 114 Justino, M. C..................................................................................................................114 Keminer, O. .....................................................................................................................58 Kijjoa, A. ................................................................................................................ 162, 167 Kiss, L............................................................................................................................166 Lacerda, P. S. S....................................................................................................... 97, 152 Lahcene, S. ...................................................................................................................170 Lahrech, M. B. ...............................................................................................................170 Langer, T. ........................................................................................................................58 Laranjo, M................................................................................................................ 74, 145 Leal, J. F........................................................................................................................103 Leite, A. ................................................................................................................... 79, 154 Lemos, A. ........................................................................................................................71 Leroy-Lhez, S. ...............................................................................................................100 Lin, Z. ............................................................................................................................151 Lobo Ferreira, A. I. M. C. .................................................................................................79 Lopes, M. M. ....................................................................................................................98 Lopes, S. M. M. ..................................................................................................... 139, 163 Lopez, O. .........................................................................................................................67 Loureiro, D. R. P. .............................................................................................................75 Lourenço, A. ....................................................................................................................99 Lourenço, L. M. O. ............................................................................. 70, 77, 129, 158, 160 Lucas, M. .......................................................................................................................104 Luís, J. P. .................................................................................................................. 52, 84 Lysenko, K. ....................................................................................................................112 M.J.Sousa, M. J. ............................................................................................................108 Macara, J................................................................................................................. 73, 147 Macatrão, M...................................................................................................................114 Maçôas, E.............................................................................................................. 120, 149 Magalhães, R. P. .............................................................................................................50 Maia, A. ................................................................................................................... 75, 155 Maia, M..........................................................................................................................166 Malafaia, D. ...................................................................................................................140 Maldonado-Carmona, N.................................................................................................100 Marcos, P. M. ................................................................................................................116 Marin, S. ........................................................................................................................142 Marques, C. F. ....................................................................................................... 113, 114 Marques, C. S..................................................................................................................59 Marques, E. F. .................................................................................................................68 Marques, F. ...................................................................................................................133 Marques, M. M............................................................................................. 58, 62, 85, 113 Marques, M. M. B. ....................................................................................... 57, 65, 73, 147 Martin, N. .......................................................................................................................120 Martínez, J. J. ................................................................................................................105 Martinho, J. M. G. .................................................................................................. 120, 149 Martini, R. ........................................................................................................................58 Martins, B. T. .................................................................................................................134 Martins, M. M. ..................................................................................................................57 Mata, A. I. ........................................................................................................................52 Mateus, N. .......................................................................................................................41 Matos, G. .........................................................................................................................97 Melo, A. .........................................................................................................................129 Mesquita, M. Q. ..................................................................................................... 122, 148 Meyrelles, R...................................................................................................................114 Miolo, G. ........................................................................................................................148 Miranda, A. S. ................................................................................................................116

177

Author index Miranda, J. P. ..................................................................................................................62 Monteiro, A. R................................................................................................................121 Monteiro, C. J. P. ................................................................................................... 148, 151 Monteiro, F. L. ....................................................................................................... 120, 170 Monteiro, S. G. ..............................................................................................................133 Morais, I...........................................................................................................................68 Morato, M. .....................................................................................................................133 Moreira, I. ......................................................................................................................154 Moreira, P. I. ....................................................................................................................86 Moreira, V. M. ............................................................................................................ 42, 92 Moura Ramos, J. J.........................................................................................................117 Moura, F. .......................................................................................................................104 Moura, N. M. M. ....................................................................................... 47, 146, 153, 159 Moura, S. ............................................................................................................... 141, 142 Moutayakine, A. .............................................................................................................168 Mullen, D. C. ....................................................................................................................92 MĂźller, C. E. .....................................................................................................................25 Murtinho, D. .....................................................................................................................83 Naouri, A. ......................................................................................................................170 Nascimento, B. F. O. .......................................................................................................74 Nascimento, M. S. J.......................................................................................................101 Neves, A. R. ....................................................................................................................43 Neves, M. G. P. M. S. ......... 70, 97, 120, 121, 122, 124, 146, 148, 149, 151, 152, 153, 159 Nogueira, D. M. ...............................................................................................................87 Nogueira, F. .....................................................................................................................68 Nunes da Silva, R. ........................................................................................... 95, 150, 155 Oliveira, I. ........................................................................................................................68 Ouahrani, M. R. .............................................................................................................170 Ouk, T.-S. ......................................................................................................................100 Overkleeft, H....................................................................................................................28 PadrĂłn, J. M. ........................................................................................................... 67, 168 Paiva, T. G.......................................................................................................................98 Palmeira, A. ........................................................................................................... 162, 166 Parkinson, J. A. ...............................................................................................................92 Paulo, A. ..........................................................................................................................35 Pedro, M. .......................................................................................................................101 Pereira, A. M. V. M. .......................................................................................................159 Pereira, C. C. L. .............................................................................................................158 Pereira, D. .....................................................................................................................134 Pereira, J. G. ...................................................................................................................88 Pereira, M. M. ............................................................................................................ 55, 61 Pereira, N. A. M. ..............................................................................................................74 Pereira, O. .....................................................................................................................108 Pereira, R. .......................................................................................................................97 Petrovski, Z......................................................................................................................76 Phyo, Y. Z......................................................................................................................162 Piccirillo, G.......................................................................................................................55 Piedade, M. F. M. ............................................................................................................96 Pineiro, M. ......................................................................................................... 74, 91, 145 Pinheiro, J. M.................................................................................................................156 Pinheiro, P. F. .......................................................................................................... 62, 114 Pinho e Melo, T. M. V. D. ............................................................. 37, 71, 74, 137, 139, 163 Pinto, D. C. G. A. ............................................................................................... 33, 81, 118 Pinto, E. .........................................................................................................................138 Pinto, M. ............................................................. 43, 75, 101, 127, 133, 134, 138, 162, 167 Pinto, P. .........................................................................................................................110

178

Author index Pinto, S. M. A...................................................................................................................61 Pires, A. S........................................................................................................................41 Poeira, D. L......................................................................................................................65 Portugal Mota, J...............................................................................................................93 Preto, A. ..........................................................................................................................64 Proença, C............................................................................................... 66, 106, 107, 132 Proença, M. F. .................................................................................................................26 Prudêncio, C. ............................................................................................................. 60, 68 Prudêncio, M. .................................................................................................. 68, 137, 139 Quaresma, S. ................................................................................................................143 Queirós, C. ......................................................................................................................79 Queiroz, M. J. R. P. .......................................................................................................136 Rakib, E. M. ...................................................................................................................153 Ramilo-Gomes, F.............................................................................................................58 Ramos, C. I. V. ...................................................................................................... 124, 153 Rangel, M. ............................................................................................................... 79, 154 Raposo, M. M. M. ............................................................................................................39 Rauter, A. P. .................................................................................................... 24, 110, 119 Reis, M. J. A. .................................................................................................................159 Reis, S. ............................................................................................................................75 Remião, F. .....................................................................................................................127 Resende, D. I. S. P. ............................................................................................... 127, 166 Ribeiro, A. P. .................................................................................................................114 Ribeiro, C. P. S. ....................................................................................................... 77, 160 Ribeiro, Daniela ............................................................................... 78, 104, 106, 107, 132 Ribeiro, Diana ................................................................................................................127 Rijo, P. ............................................................................................... 54, 72, 135, 143, 144 Rocha, D. H. A...............................................................................................................170 Rocha, G. ........................................................................................................................53 Rocha, J. ........................................................................................... 51, 95, 150, 155, 161 Rocha, S.................................................................................................................. 89, 106 Rodrigues, C. A. B. ........................................................................................................105 Rodrigues, F. M. S. ..........................................................................................................82 Roleira, F. M. F. .............................................................................................................132 Romanelli, G. P. ............................................................................................................105 Rosado, C........................................................................................................................93 Rosado, P. C. ................................................................................................................114 Saher, L. ........................................................................................................................170 Salvador, J. A. R.............................................................................................. 86, 141, 142 Santos de Almeida, D. ...................................................................................................108 Santos de Almeida, T. .....................................................................................................93 Santos, A. E.....................................................................................................................86 Santos, A. O. ...................................................................................................................40 Santos, A. S.....................................................................................................................57 Santos, C.........................................................................................................................87 Santos, C. I. M. ...................................................................................................... 120, 149 Santos, C. M. M. ..............................................................................................................66 Santos, F. ........................................................................................................................76 Santos, L. M. N. B. F. ......................................................................................................79 Santos, M. J. G. .............................................................................................................155 Santos, M. M. ..................................................................................................................76 Santos, N. E. .................................................................................................................123 Saraiva, N........................................................................................................................93 Sarmento, B........................................................................................................... 131, 158 Sarmin, A.........................................................................................................................92 Sathicq, A. G. ................................................................................................................105

179

Author index Schaberle, F. .................................................................................................................126 Sena, A............................................................................................................................67 Serra, M. E. S. .................................................................................................................83 Serra, S. G.....................................................................................................................146 Serrano, J. .......................................................................................................................40 Severino, V. G. P. ..........................................................................................................109 Shimizu, K. ....................................................................................................................114 Shroder, R. ......................................................................................................................76 Silva, A. M. G........................................................................................................... 79, 154 Silva, A.M.S.44, 51, 66, 78, 81, 95, 106, 107, 118, 128, 140, 150, 155, 161, 162, 167, 170 Silva, A. T. .......................................................................................................................68 Silva, B. R......................................................................................................................136 Silva, C. F. M. ................................................................................................................118 Silva, D. ..................................................................................................................... 76, 96 Silva, E. R........................................................................................................................43 Silva, L. B. .....................................................................................................................110 Silva, M..........................................................................................................................102 Silva, M. I. S. C. .............................................................................................................109 Silva, M. J. S....................................................................................................................63 Silva, M. M. C. .................................................................................................................86 Silva, P. P. M. A.............................................................................................................127 Silva, R. .........................................................................................................................127 Silva, V. L. M. ...................................................................................... 44, 78, 79, 123, 128 Silvestre, S. ............................................................................................................. 40, 156 Simão, J. L. S. ...............................................................................................................109 Simeonov, S. P. .............................................................................................................105 Simões, C. J. V. ................................................................................................. 52, 84, 137 Soares, J. X. ....................................................................................................................75 Soares, M. I. L. ..............................................................................................................139 Soares-da-Silva, P. ..........................................................................................................36 Sobral, L. .........................................................................................................................58 Sobral, P. J. M. ...................................................................................................... 141, 142 Sousa, A. ................................................................................................................. 78, 155 Sousa, C..........................................................................................................................49 Sousa, E. ................................................................................. 43, 127, 133, 138, 166, 167 Sousa, S. F. .....................................................................................................................50 Stark, H. ........................................................................................................................168 Talhi, O. ................................................................................................................... 90, 170 Tavares, N. C. T. .............................................................................................................83 Taveira, N. ............................................................................................................. 137, 139 Tedjini, R. ........................................................................................................................90 Teixeira, A. P. S.............................................................................................................102 Teixeira, C. ................................................................................................................ 60, 68 Teixeira, J. .....................................................................................................................162 Teixeira, M. ....................................................................................................................101 Tessari, F.......................................................................................................................148 Tiritan, M. E. ..................................................................................................................162 Tomé, A. C. ..................................................................................... 70, 124, 157, 164, 165 Tomé, J. P. C........................................................................... 70, 129, 130, 131, 158, 160 Tomé, S. M. ...................................................................................................................107 Tomé, V. A.......................................................................................................................61 Torres, T. .........................................................................................................................23 Trindade, T. ............................................................................................................. 97, 121 Udomsak, W. .................................................................................................................167 Valdeira, A. S. C. ...........................................................................................................141 Valente, A. .......................................................................................................................64

180

Author index Vallejo, M. C. S. .............................................................................................................146 Varela, C .......................................................................................................................132 Vasconcelos, M. H. ........................................................................................................136 Vasconcelos, V. ...............................................................................................................43 Vaz Serra, V. .................................................................................................................146 Vaz, P. A. A. M. ...............................................................................................................51 Veiros, L. F. ............................................................................................................. 63, 125 Viciosa, M. T. .................................................................................................................117 Vieira, S. I. .....................................................................................................................155 Vieira, T. F. ......................................................................................................................50 Villandier, N. ..................................................................................................................100 Vinagreiro, C. S. ............................................................................................................126 Viveiros, R. ......................................................................................................................90 Woldemichael, G. M. .....................................................................................................141 Xavier, C. P. R. ..............................................................................................................136 Xavier, J. .......................................................................................................................104 Xavier, N. M. ....................................................................................................................56 Young, L. .........................................................................................................................92 Zanatta, M. ......................................................................................................................98

181

O Campus de Santiago

LIST OF PARTICIPANTS

List of participants

A Adelaide Patrícia Teles de Sousa Faculdade de Farmácia da Universidade do Porto / LAQV-REQUIMTE adelaidetsousa@gmail.com

Ana Margarida Gomes da Silva LAQV/REQUIMTE, Dept de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto ana.silva@fc.up.pt

Alexandra Maria Moita Antunes Instituto Superior Técnico alexandra.antunes@tecnico.ulisboa.pt

Ana Rita Leite Araújo Universidade de Aveiro anararaujo@ua.pt

Alexandra Paulo iMed. Universidade de Lisboa mapaulo@ff.ulisboa.pt

Ana Rita Rodrigues Vilares Cabral Monteiro Universidade de Aveiro anarita.rvcm@ua.pt

Alice Dias Universidade do Minho ad@quimica.uminho.pt

Ana Sofia Branco dos Santos Faculdade de Ciências e Tecnologias - UNL asb.santos@campus.fct.unl.pt

Amelia Pilar Grases Santos Silva Rauter Faculdade de Ciências, UNiversidade de Lisboa aprauter@fc.ul.pt

Ana Sofia Marques Joaquinito Universidade de Aveiro a.joaquinito@ua.pt

Americo José dos Santos Alves University of Coimbra americo.jsa.92@gmail.com

Anthony J Burke Universidade de Evora ajb@uevora.pt

Amina Moutayakine Universidad Evora amina.moutayakine@gmail.com

Artur Manuel Soares da Silva Universidade de Aveiro artur.silva@ua.pt

Ana Cristina da Silva Fernandes Centro de Química Estrutural, IST, Universidade de Lisboa anacristinafernandes@tecnico.ulisboa.pt

Augusto Costa Tomé Universidade de Aveiro actome@ua.pt

Ana Filipa Reis Cerqueira Universidade de Aveiro anacerqueira@ua.pt

Bruno Filipe Oliveira Nascimento CQC e Departamento de Química, Universidade de Coimbra bfonascimento@gmail.com

Ana Isabel Gomes da Mata Universidade de Coimbra ana.mata@student.uc.pt

Bruno Vasco Luís Franco Faculdade de Ciências e TecnlogiaUniversidade Nova de Lisboa b.franco@campus.fct.unl.pt

Ana Lúcia Cabral Cardoso Lopes Departamento de Química, Universidade de Coimbra analcclopes@gmail.com

C Carina Isabel Coelho Proença LAQV-REQUIMTE, Faculdade de Farmácia da Universidade do Porto carina.proenca.tas@gmail.com

Ana Luísa Gomes Júlio CBIOS-Center for Research in Biosciences & Health Technologies, Universidade Lusófona de Humanidades e Tecnologias analuisajulio@gmail.com

183

List of participants Carla Isabel Madeira Santos Instituto Superior Técnico & Universidade de Aveiro cims@ua.pt

Cátia Filipa Sousa Marques Centro de Química Estrutural catiaf_marques@hotmail.com Cátia Isabel Canavezes Esteves Universidade de Aveiro catiaiesteves@ua.pt

Carla Sofia Garcia Fernandes Faculdade de Farmácia da Universidade do Porto cfernandes@ff.up.pt

Cátia Teixeira LQV-REQUIMTE Faculdade de Ciências da Universidade do Porto catia.teixeira@fc.up.pt

Carla Sofia Loureiro Gomes University of Coimbra carla_sofia.gomes@live.com.pt

Christa E. Müller Department of Pharmaceutical & Medicinal Chemistry christa.muller@uni-bonn.de

Carla Thaís Pereira Coelho Universidade Federal de Goiás carlathaispc19@gmail.com Carlos Alberto Mateus Afonso Faculdade de Farmácia da Universidade de Lisboa carlosafonso@ff.ulisboa.pt

Cláudia Daniela da Cruz Alves Universidade de Coimbra claudialves2094@gmail.com Cláudia Patrícia Santos Ribeiro Universidade de Aveiro claudia.santos.ribeiro7@ua.pt

Carlos Fábio Magalhães da Silva Universidade de Aveiro silva.c@ua.pt

Clementina M. M. Santos Instituto Politécnico de Bragança clems@ipb.pt

Carlos Jorge Pereira Monteiro Universidade de Aveiro cmonteiro@ua.pt

Cristina Jesus Dias Universidade de Aveiro cristina.jesus.dias@ua.pt

Carlos Miguel Calisto Baleizão Centro de Química Estrutural - Instituto Superior Técnico carlos.baleizao@tecnico.ulisboa.pt

D Daniela Filipa Pereira Silva Centro de Química Estrutural IST-ID daniela.filipa.2710@hotmail.com

Carmen Maribel Bento Teixeira Instituto Univesitário de Ciências da Saúde (Grupo CESPU) maribel.teixeira@iucs.cespu.pt

Daniela Maria Vilaça Pereira Faculdade de Farmácia da Universidade do Porto danielapereira.23@hotmail.com

Carolina Silva Marques Universidade de Évora carolsmarq@gmail.com

Daniela Raquel Pontes Loureiro Faculdade de Farmácia da Universidade do Porto daniela.rpl93@gmail.com

Catarina Garcia Bravo Centro de Química Estrutural IST-ID catarinabravo6@gmail.com Catarina Isabel Vicente Ramos University of Aveiro c.ramos@ua.pt

Daniela Sofia Almeida Ribeiro LAQV-REQUIMTE, Faculdade de Farmácia da Universidade do Porto dsribeiro@ff.up.pt

184

List of participants Declan Mullen University of Strathclyde declan.mullen@strath.ac.uk

Graça Maria da Silva Rodrigues Oliveira Rocha Universidade de Aveiro grrocha@ua.pt

Diana Cláudia Gouveia Alves Pinto Universidade de Aveiro diana@ua.pt

H Hélio Manuel Ferreira Faustino Research Institute for Medicines (iMed.ULisboa) heliofaustino@gmail.com

Diana Isabel Soares Pereira Resende CIIMAR - Interdisciplinary Centre of Marine and Environmental Research dresende@ff.up.pt

Hélio Miguel Teixeira Albuquerque University of Aveiro helio.albuquerque@ua.pt

Dina Maria Bairrada Murtinho Universidade de Coimbra dimur@net.sapo.pt

Herman Overkleeft Leiden Institute of Chemistry h.s.overkleeft@chem.leidenuniv.nl

Diogo Alexandre Vilaça Lopes Universidade de Aveiro diogoavl@ua.pt

Hermínio Albino Pires Diogo Instituto Superior Técnico- Lisboa hdiogo@tecnico.ulisboa.pt

Diogo Lopes Poeira Faculdade de Ciências e TecnlogiaUniversidade Nova de Lisboa d.poeira@campus.fct.unl.pt

J Joana Filipa Brites Barata CESAM, Universidade de Aveiro jbarata@dq.ua.pt

E Elisabete Palma Carreiro Universidade de Évora bete_carreiro@yahoo.com

Joana Ferreira Leal Centre of Marine Sciences, University of Algarve jfleal@ualg.pt

F Fausto Daniel dos Santos Queda Faculdade de Ciências e TecnlogiaUniversidade Nova de Lisboa f.queda@campus.fct.unl.pt

Joana Maria Duarte Calmeiro Universidade de Aveiro jcalmeiro@ua.pt Joana Raquel Mendes Ferreira Universidade de Aveiro joanarmf@ua.pt

Fernanda Borges CIQUP/Department of Chemistry and Biochemistry fborges@fc.up.pt

João António iMed.ULisboa jpantonio2@hotmail.com João Conde iMM- Universidade de Lisboa joaodconde@gmail.com

Filipa Ramilo-Gomes Instituto Superior Técnico - Universidade de Lisboa filipa.ramilo@gmail.com

João Cristóvão Santos Silva Macara Faculdade de Ciências e TecnlogiaUniversidade Nova de Lisboaj.macara@campus.fct.unl.pt

G Giulia Francescato ITQB NOVA giulia.francesc@gmail.com

185

List of participants João Paulo Costa Tomé Instituto Superior Técnico - Universidade de Lisboa jtome@tecnico.ulisboa.pt

Leonardo Mendes Sociedade Portuguesa de Química leonardo.mendes@spq.pt Leonor de Sá Nogueira Côrte-Real Faculdade de Ciências da Universidade de Lisboa ldcortereal@fc.ul.pt

João Paulo de Sousa Ferreira Universidade de Aveiro joao.paulo.sousa.f.96@gmail.com João Pedro dos Reis Luís Departamento de Química da Universidade de Coimbra jluis@student.ff.uc.pt

Letícia Daniela da Silva Costa University of Aveiro leticia.costa@ua.pt Lídia Alexandra Santos Cavaca Faculdade de Farmácia, Universidade de Lisboa l.cavaca@ff.ulisboa.pt

Jorge António Ribeiro Salvador Faculdade de Farmácia da Universidade de Coimbra salvador@ci.uc.pt

Liza Saher University of Aveiro liza.saher@ua.pt

José Abrunheiro da Silva Cavaleiro Universidade de Aveiro jcavaleiro@ua.pt

Luciana Barbosa da Silva Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa lbsilva@fc.ul.pt

José Gonçalo Deira Duarte de Campos Justino Instituto Superior Técnico goncalo.justino@tecnico.ulisboa.pt José Miguel Pimenta Ferreira de Oliveira LAQV-REQUIMTE, Faculdade de FarmáciaUniversidade do Porto jmoliveira@ff.up.pt

Luis Alexandre Almeida Fernandes Cobra Branco LAQV-REQUIMTE, Faculdade de Ciências e Tecnlogia- Universidade Nova de Lisboa l.branco@fct.unl.pt

Judite Raquel Martins Coimbra Faculty of Pharmacy, University of Coimbra coimbra.jrm@gmail.com

Luís Filipe Baptista Fontes Universidade de Aveiro lfontes@ua.pt

Juliana Gomes Pereira iMed. ULisboa julianagpereira92@gmail.com

Luis Miguel Neves Ferreira Serra Cruz Faculdade de Ciências da Universidade do Porto luis.cruz@fc.up.pt

Luísa Maria da Silva Pinto Ferreira Faculdade de Ciências e TecnlogiaUniversidade Nova de Lisboa lpf@fct.unl.pt

Karyna Lysenko Universidade de Aveiro karynalysenko@ua.pt

Maria da Graça de Pinho Morgado Silva Neves University of Aveiro grneves@dq.ua.pt

Leandro Miguel de Oliveira Lourenço University of Aveiro leandrolourenco@ua.pt

186

List of participants Maria de Fátima M. M. Minas da Piedade CQE, IST-DQB, Faculdade de Ciências Universidade Nova de Lisboa mdpiedade@fc.ul.pt

Maria Manuel Martinho Sequeira Barata Marques Faculdade de Ciências e TecnlogiaUniversidade Nova de Lisboa msbm@fct.unl.pt

Maria de Lurdes Cristiano Universidade de Algarve mcristi@ualg.pt

Maria Manuela Marques Raposo Universidade do Minho mfox@quimica.uminho.pt

Maria do Amparo Ferreira Faustino Universidade de Aveiro faustino@ua.pt

Maria Matilde Soares Duarte Marques Instituto Superior Técnico matilde.marques@tecnico.ulisboa.pt

Maria Elisa da Silva Serra Dep. Química, Universidade de Coimbra melisa@ci.uc.pt

Maria Miguéns Pereira Universidade de Coimbra mmpereira@qui.uc.pt

Maria Emília da Silva Pereira de Sousa Faculdade de Farmácia da Universidade do Porto esousa@ff.up.pt

Mariana Filipa Mendes Lucas LAQV, REQUIMTE, Laboratório de Química Aplicada, Faculdade de Farmácia, Universidade do Porto mariana_lucas1994@hotmail.com

Maria Fernanda Proença CQ-UM and Department of Chemistry fproenca@quimica.uminho.pt

Mariana Queirós Mesquita Universidade de Aveiro marianamesquita@ua.pt

Maria Inês Figueiredo Moreira LAQV-REQUIMTE, Departamento de Química e Bioquímica da Faculdade de Ciências da Universidade do Porto mariainesfm@fc.up.pt

Mariana Vallejo Universidade de Aveiro mariana.vallejo@ua.pt

Maria Isabel Ismael Universidade Beira Interior iismael@ubi.pt

Marina Costa Universidade de Évora marinamcosta91@gmail.com

Maria Isabel Lopes Soares Universidade de Coimbra misoares@ci.uc.pt

Mário José Ferreira Calvete Universidade de Coimbra mcalvete@qui.uc.pt

Maria João Ribeiro Peixoto de Queiroz Universidade do Minho mjrpq@quimica.uminho.pt

Mário Manuel Quialheiro Simões University of Aveiro msimoes@dq.ua.pt

Maria Manuel Duque Vieira Marques dos Santos Faculdade de Farmácia - Universidade de Lisboa mariasantos@ff.ulisboa.pt

Marisa Andreia Carvalho de Freitas LAQV-REQUIMTE, Faculdade de Ciências e Tecnlogia- Universidade Nova de Lisboa marisafreitas@ff.up.pt Marta Correia da Silva CIIMAR, Universidade do Porto m_correiadasilva@ff.up.pt

187

List of participants Marta Pineiro Universidade de Coimbra mpineiro@qui.uc.pt

Patrícia Rijo Universidade Lusófona de Humanidades e Tecnologias patricia.rijo@ulusofona.pt

Melani Joana Almeida Reis Universidade de Aveiro melani@ua.pt

Patrício Soares da Silva BIAL Psoares.silva@bial.com

Miguel Araújo Maia CIIMAR, Universidade do Porto miguelmaia2@gmail.com

Paula Alexandra de Carvalho Gomes Universidade do Porto - Faculdade de Ciências pgomes@fc.up.pt

Miguel Bernardo Instituto Superior Técnico miguelmbernardo@tecnico.ulisboa.pt

Paula Cristina Alves Marques Centro de Química Estrutural IST-ID paula.alves.marques@tecnico.ulisboa.pt

N Nélia Cristina Tadeu Tavares Universidade de Coimbra neliatadeu@hotmail.com

Paula Cristina de Sério Branco Faculdade de Ciências e TecnlogiaUniversidade Nova de Lisboa paula.branco@fct.unl.pt

Nidia Maldonado-Carmona Universidade de Coimbra / Université de Limoges nidia.maldonado@etu.unilim.fr

Paula Maria de Jorge Marcos Faculdade de Farmácia – Universidade de Lisboa pmmarcos@fc.ul.pt

Nuno Alexandre Guerreiro Alves Universidade de Coimbra nunoagalves@gmail.com

Paula Sofia Sarrico Lacerda Universidade de Aveiro placerda@ua.pt

Nuno Filipe Rafael Candeias Universidade de Aveiro nuno.rafaelcandeias@tuni.fi

Paulo Jorge dos Santos Coelho Universidade de Trás-os-Montes e Alto Douro pcoelho@utad.pt

Nuno Manuel Ribeiro Martins Xavier Faculdade de Ciências, Universidade de Lisboa nmxavier@fc.ul.pt

Paulo Ricardo Ribeiro Cristelo Faculdade de Farmácia da Universidade do Porto ricardorc@live.com.pt

Nuno Miguel Malavado Moura Universidade de Aveiro nmoura@ua.pt

Pedro da Conceição Rosado Centro de Química Estrutural - Instituto Superior Técnico pedrocrosado@tecnico.ulisboa.pt

P Patricia Alexandra Amaro Martins Vaz Universidade de Aveiro patriciavaz@ua.pt

Pedro Franco Pinheiro Instituto Superior Técnico pedro.pinheiro@tecnico.ulisboa.pt

Patrícia Ferreira Calado Faculdade de Ciências da Universidade de Lisboa patriciacalado95@hotmail.com

188

List of participants Pedro José Moreira Sobral Faculdade de Farmácia da Universidade de Coimbra pedrojmsobral@gmail.com

Rui Moreira Faculdade de Farmácia da Universidade de Lisboa rmoreira@ff.ulisboa.pt

Pedro M. P. Góis iMed.ULisboa pedrogois@ff.ul.pt

Rui Pedro Santos Rachão Faculdade de Ciências da Universidade do Porto rui_rachao@hotmail.com

Pedro Manuel da Costa Gomes Brandão CQC and Department of Chemistry, University of Coimbra pedrocgbrandao@gmail.com

S Samuel Guieu Universidade de Aveiro sguieu@ua.pt

Pedro Nuno Leal Palma BIAL nuno.palma@bial.com

Samuel Martins Silvestre Universidade da Beira Interior samuel@fcsaude.ubi.pt

R Rafael Filipe Teixeira Arbuez Gomes iMed.Ulisboa rafaelgomes92@live.com.pt

Sandra Cristina Amaro Beirão Instituto Superior Técnico sandrabeirao@tecnico.ulisboa.pt

Rafael Tiago Pereira Martins Aroso Universidade de Coimbra rafael.aroso.94@gmail.com

Sara Crisitina Nobre Garcia Instituto Superior Técnico saracngarcia@gmail.com

Raquel Alexandra Valadares Barrulas Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa r.barrulas@campus.fct.unl.pt

Sara Martinho Almeida Pinto Universidade de Coimbra smpinto@qui.uc.pt Sara Patrícia de Sousa Pereira Moura Faculdade de Farmácia da Universidade de Coimbra spmoura17@gmail.com

Raquel Sofia de Oliveira Nunes da Silva University of Aveiro rsons@ua.pt Ricardo João Vieira Ferraz Escola Superior de Saúde do Instituto Politécnico do Porto ricardoferraz@eu.ipp.pt

Sara Raquel Duarte Gamelas Universidade de Aveiro sara.gamelas@ua.pt Sara Raquel Gomes Fernandes Instituto Superior Técnico, Universidade de Lisboa sararfernandes@tecnico.ulisboa.pt

Ricardo Miguel Ribeiro Magalhães Lopes Faculdade de Farmácia, Universidade Nova de Lisboa rmr.lopes@campus.fct.unl.pt

Sérgio Filipe Maia de Sousa UCIBIO/REQUIMTE, Universidade do Porto sergiofsousa@med.up.pt

Rima Tedjini University of Lisbon, FCT/UNL r.tedjini@campus.fct.unl.pt

Sónia Aguiar da Rocha Faculdade de Farmácia- Universidade do Porto soniaarocha@ua.pt

Rui Loureiro Hovione rloureiro@hovione.com

189

List of participants Sónia Maria Gomes Pires University of Aveiro sonia.pires@ua.pt

Véronique Gouverneur University of Oxford veronique.gouverneur@chem.ox.ac.uk

Susana Margarida Martins Lopes Centro de Química Estrutural and Departament of Chemistry, University of Coimbra smlopes@uc.pt

Victor Freitas Universidade do Porto vfreitas@fc.up.pt Vítor Alexandre da Silva Almodôvar Universidade de Aveiro almodovar_vitor@hotmail.com

Susana Paula Graça da Costa Universidade do Minho spc@quimica.uminho.pt

Susana Santos Braga University of Aveiro sbraga@ua.pt

Wachirawit Udomsak Khon Khan University wachirawit5414@gmail.com

Yonah Favero Gérios Instituto Politécnico de Bragança joaos@ipb.pt

Teresa Margarida Vasconcelos Dias de Pinho e Melo University of Coimbra tmelo@ci.uc.pt Tomás Torres Department of Organic Chemistry, Universidad Autonoma de Madrid tomas.torres@uam.es

V Vanessa Isabel Macedo Araújo Universidade de Aveiro Vmacedo@ua.pt Vania M. Moreira CNC, Faculdade de Farmácia da Universidade de Coimbra vmoreira@ff.uc.pt Vânia Mafalda de Oliveira André Instituto Superior Técnico-ID, CQE vaniandre@tecnico.ulisboa.pt Vasco Figueiredo Batista Universidade de Aveiro vfb@ua.pt Vera Lúcia Marques da Silva University of Aveiro verasilva@ua.pt

190