Synthesis and characterization of

SYNTHESIS AND CHARACTERIZATION OF CHLOROQUINE CLICK DERIVATIVES WITH POTENTIAL ANTIMALARIAL ACTIVITY

Author: Marko Dužević Scientific Coordinator: doc. dr. sc. Ivana Perković Institution: Faculty of Pharmacy and Biochemistry at University of Zagreb

Malaria is one of the most prevalent parasitic diseases in the world, ranked by the WHO in 2016 as the 6th most common cause of death in low-developed countries. Although positive progress has been made in its treatment and prevention over the past decade, there is still a great need for the development of new antimalarials due to the emergence and spread of strains resistant to conventional drugs. Until the advent of newer molecules, in the past, due to its good safety profile, efficacy, and cost-effective synthesis, chloroquine was used very often and is still used today as a model drug for the development of new alternative antimalarials. To enhance its antiplasmodial activity on resistant strains, four new quinoline-1H-1,2,3-triazole hybrids with harmine, an alkaloid of plant origin that also has antimalarial activity, were synthesized using method of copper-catalysed azide–alkyne cycloaddition. The reactions of organic azides and alkynes catalysed by copper species represent the prototypical examples of click chemistry. This paper presents the procedures for their synthesis and the results of structural characterization by analytical and spectroscopic techniques. All synthesized compounds have shown the potential for good oral bioavailability, and further research, which goes beyond the scope of this paper, will examine their antiparasitic effects on species of the genus Plasmodium.

Newly synthesised molecules presented in the paper

Questions & answers

Please, tell us a little bit more about yourself. I was born on March 29, 1998, in the capital of Croatia Zagreb. In 2016 I enrolled at the Faculty of Pharmacy and Biochemistry at the University of Zagreb and now I am in my fifth-year. Immediately at the beginning of my studies, I have become a member of the Croatian Pharmaceutical Students’ Association (CPSA), within which I regularly participate in activities and events related to the pharmaceutical profession. In the academic year 2018/19, I was elected Secretary of the Association for a term of one year. In the same year, I had become a demonstrator at the Department of Organic Chemistry and one of the organizers of the CPSA’s National Congress. As an educational coordinator, I was responsible for choosing lectures’ topics and finding lecturers. In my fourth year, I decided to make a run for a member of the Student Union of the University of Zagreb to represent the students, fighting for their rights, and raising the students’ standard. I was elected to this position for a term of 2 years. In the same year, I joined the preparation of this scientific paper because of my interest in the development and synthesis of new drugs. The main motive for joining the research group at the Department of Medicinal Chemistry on my home faculty was a desire to acquire new knowledge and skills in the field of synthetic pharmaceutical chemistry and to start a scientific career. For this paper, I was awarded the Rector’s Award in 2020.

Tell us a bit more about your research and its significance. My research was conducted in the Department of Medicinal Chemistry and was part of the Department’s project entitled “Harmine derivatives as potential antimalarials”. It was planned for me to synthesize seven new compounds, but, due to lockdown in March, research lasted only 5 months and it encompassed synthesis and characterization of only four imaginary compounds. Structures of all the newly-synthesized molecules were confirmed using conventional analytical techniques such as nuclear magnetic resonance, IR, and mass spectroscopy. In the scientific paper are adduced methods and materials used for their synthesis. Furthermore, it contains ADME properties prediction carried out using SwissADME online tool. This research could be important if further in vitro assays would prove compounds’ antimalarial activity. If that happens, one of these molecules could be used as a lead compound and its optimization could lead to the invention of new antimalarial for Plasmodium strains resistant to conventional therapy.

What was the biggest challenge whilst carrying out the research and how did you overcome it? The biggest challenge was to perform faculty duties parallelly throughout the duration of the research. Since my lectures, seminars, and laboratory exercises were obligatory, I couldn’t skip teaching to have more time for synthesis. Unfortunately, I wasn’t able to overcome this problem, so I just got used to it. Ten hours at the faculty was my everyday life and the only time when I could do quality learning was on weekends. Another problem was the fact that you can’t leave the laboratory until you finish synthesis or previously started the compound purification process. The workday ends when you pack your final product for NMR analysis. Fortunately, one of the assistants and I had an agreement: some days he was finalizing my compounds and the other days it was my turn to help him. Although this research was a very stressful period for me, I can tell that it was also a wonderful period because I learned incredibly much in those 5 months.

In your opinion, what is the benefit of joining ESSP and what advice do you have for students undertaking research in the future? For me, the biggest benefit of joining ESSP is the possibility of this platform to bring your work to a wider audience. By sharing our knowledge we enrich the community and make knowledge accessible to everyone. Also, by publishing our work we help others solve or avoid problems that we were struggling with during our research. Just like any other passion, research also demands huge dedication and effort, but the final results and joy you feel are something that one lives for.