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Research & Reviews: A Journal of Drug Design & Discovery

Contents

1. Drug Designing and Research: Ayurvedic Approach Nishant Shukla

2. Synthesis and Anti-Bacterial Activity Profile of Cyclized Diazonium Compounds Priti Jain, L. Naga Rajiv, Hemant R. Jadhav

3. Targeting Cancer through Angiogenesis Inhibition: Prospective of Azole Based Small Molecules Pratap Chandra Acharya

Research & Reviews: A Journal of Drug Design & Discovery Volume 1 Issue 1 www.stmjournals.com

Drug Designing and Research: Ayurvedic Approach Nishant Shukla* Morjand Khari, Sriganganagar, Rajasthan Abstract Ayurveda the ancient Indian medical wisdom has served society through its holistic approach of healing. Ancient Indian scientists Acharya Charaka, Acharya Sushruta, etc. has done in drug research and clinical research. This approach was not only aims to treat a person but to bring the original state. Acharya Charaka clarifies that a physician or researcher ought to look at least four whilst treatment the patient i.e. roga bala (therapeutic effect on disease), deha bala (strength or immunity), chitta bala (psyche) and agni bala (digestion & metabolism). Herbs used ought to have at least four properties i.e. bahu kalpap, bahu gunam, sampanna and yogya. Preparation of poly-herbal, herbo-mineral combination ought to be done as per the norms prescribed by Acharya Charaka. Individualized approach of drug delivery is necessary and research needs to incorporate them. The paper discuss these in details.

Keywords: Ayurveda, Drug designing, poly-herbal, herbo-mineral

*Author for Correspondence E-mail: nishantvd@rediffmail.com INTRODUCTION Drug designing is extremely important in medical research. It is even more important in Ayurveda system of medicine, where numerous combination herbal, herbo-minerals, herb-animal compounds are prepared and used. Effect of individual drugs were studied and documented in ancient classics like Charaka Samhita, Sushruta Samhita, Astang Hridya, Nighantus, etc. latest work done in this field is by Acharya Bhavmishra in 18th century. Many combinations were made by different scholar in past based on their observations and experiences, this is practiced in present era also to search for better alternate. Owing to the fact that diseases are always multifactorial and group of symptoms instead of using single herb combinations were prepared and experimented. Today there are more than ten thousand poly-herbal, herbomineral compound in use for ayurvedic medical management. The quest is continuing, and new formulations are prepared, experimented, used clinically.

physiology as body & mind are interdependent. One must attend to holistic approach while preparing any new poly-herbal or herbo-mineral combination. Other primary requisite mentioned in the classics is a drug must treat disease and at the same time should not alter other doshas. In order to achieve the above mentioned goal Acharya Charaka gave guidelines i.e. physician must examine at least four aspects very minutely whilst treating patient i.e. yoga Bala (strength/severity/gravity /stage of disease), Deha Bala (body strength & immunity), Chitta Bala (psychological wellbeing) and Agni Bala (digestion & metabolism)[1]. This paper will highlight ayurvedic principles for designing a polyherbal medicine.

KNOWLEDGE AND RESEARCH GAPS Preparation of SOP (standard operative procedure) for Designing of poly-herbal formulation is ought to be made from the guidelines described in ayurvedic classics. This is hurdle in scientific approach of drug planning.

Drug designing requires detailed study of human body and drugs used. Human body is not physical only; psyche affects bodyâ&#x20AC;&#x2122;s

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Drug Designing & Research Nishant Shukla __________________________________________________________________________________________

AIMS AND OBJECTIVE A review paper on scientific designing of poly-herbal ayurvedic medicines was presented with following aims & objectives 1. Study of ayurvedic principle for drug research 2. SOP for drug designing

MATERIALS & METHODS Review paper was based on scientific evidences available in ancient ayurvedic classics and it’s through study and develops a SOP from the guidelines.

AYURVEDIC APPROACH TO DRUG RESEARCH Acharya Charaka and Acharya Bhavmishra has been described the study of herbs and Acharya Sharangdhar described guidelines for drug preparation. This is not completely followed in the present practice and most of the drugs are combined with keeping in view of their chemical constituent. Moreover drugs used today are prepared from plant extracts (mostly alcoholic). Ancient scholars used drug as a whole and extracts used were water extracts only. Use of whole plant is having added benefit over its extract; the greatest example is sarpagandha (Rauvolfia serpentina‎) roots when used as whole plant has no adverse drug reactions like – suicidal tendency, bradycardia, drowsiness, etc. and controls blood pressure. But the use of its extracted alkaloid serpentine (reserpine) produces adverse drug reaction similar adverse effect is observed in sarpagandha ghanvati too. Ayurvedic drug research is based on pharmaceutical (bahukalpam), pharmacologica l (bahugunam), pharmacognosical (sampanam) and therapeutically potent (yogyam) [2]. As discussed above a physician ought to see deha bala, chitta bala and agni bala, Acharya Charaka clarified this in viman 8 whilst describing karyafala (outcome of treatment). Acharya Charaka described that a drug is said to be effective if it heals disease and ought to improve complexion, physical strength and immunity, regulate digestion & metabolism, regular sleep and awakening i.e. it should also improve general wellbeing of the patient [3]. It is observed in contemporary science that drug whilst correcting illness produce adverse drug reaction or idiosyncrasies; some are even more

dangerous than the primary illness for instance quinine used for treatment of malaria may produce ITP, acute renal failure. Amodiaquine may have agranulocytosis, Amodiaquine may produce intravascular hemolysis over and above gastric disturbance, headache, irregularities, etc. The cited idiosyncrasies are only the example and most of drug used have such adverse effects, owing to these adverse drug reaction FDA has proscribed various drugs, so research in the medicine ought to be based on approach of Acharya Charaka. Importance of prakriti and vikriti [4] in clinical medicine has been acknowledged in ayurvedic medicine. Ayurvedic medicines are grouped as vyadhi-hara, dosha-hara and ubhaya-hara. 1. Vyadhi-hara means a drug has effect on disease i.e. corrects dosha-dushya sammurchana (as dosha-dushya sammurchana is the important event in disease production) and can be used irrespective of prakriti of individual, doshas involved for instance most of herbo-mineral compounds are of this nature, vatsanabh (Aconitum ferox) in jwara, pushkarmula (I. racemosa) in chest pain, somalata in asthma, etc. A physician can prescribe this medicine use these medicines with observing only the age and gravity of disease for dosage. 2. Dosha-hara means drug that corrects dosha. It through medical examination – ten fold examinationiv and analyze morbid medical condition on doshik paradigm [5– 6]. This is used in ayurvedic practice and needs perfection in clinical examination minute observation is prerequisite. 3. Ubhaya-hara means these are such drugs which not only corrects the dosha primarily involved in disease but also corrects dosha-dushya saamurchana, for example use of dashmula kwath vatic sotha (pitting edema) is vata shamak and shothaghana (anti-inflammatory). These drugs are combinations are appreciated as has dual action. This concept of ayurveda is not accepted in previous years, but concept of individualized care is now accepted for research purpose also. A recent research on rheumatoid arthritis carried out by Ramesh C. Juyal and his team validated concept of prakriti and its

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Research & Reviews: A Journal of Drug Design & Discovery Volume 1, Issue 1 __________________________________________________________________________________________

importance in clinical efficacy of the drug. The conclusion drawn by them clarifies this concept they concluded that “This exploratory study suggests discrete causal pathways for RA etiology in prakriti based subgroups, thereby, validating concepts of prakriti and personalized medicine in Ayurveda. Ayurgenomics approach holds promise for biomarker discovery in complex diseases”[7].

3. Achrya

SUMMARY Drug designing and drug research has been unique approach in ayurveda and not only objected to treat disease but to bring back normalcy after treatment, it covers all the three component of body. This holistic approach reduces probabilities of adverse drug reaction or idiosyncrasies. Research in Ayurveda ought to be based on ayurveda principles to validate the facts described in ayurvedic treatises.

REFERENCE 1. Achrya Charaka,

Charaka Samhita, Niryana Sagar press third edition.1941: Ch. Ni. 8/36-37 “ ddhisth na ṣay as th ṁ ōg ṇ mupala ṣayēt| susū ṣm mapi ca p jñō dēh gnibalacētas m||36|| y dhy a asth iśēṣ n hi jñ t jñ t vicakṣaṇaḥ| tasy ṁ tasy ma asth y ṁ catuḥś ēyaḥ p apadyatē||37|| 2. Achrya Charaka, Charaka Samhita, Niryan a Sagar press third edition.1941: Ch. Su. 9/7 ”bahut tat ayōgyat amanē a idha al pan | sampaccēti catuṣ ō'yaṁ d a y ṇ ṁ guṇa ucyatē||7||

Charaka, Charaka Samhita, Niryana Sagar press third edition. 1941: Ch. Vi. 8/89 “ yaṁ dh tus myaṁ, tasya la ṣaṇaṁ i ōpaśamaḥ| pa ī ṣ t asyaugupaśamanaṁ, s a a a ṇayōgaḥ, śa ī ōp acayaḥ, bala ddhiḥ, abhya ah y bhil ṣa ḥ, uci h a lē, abhya ah tasya c h asy a kale samyagja aṇaṁ, nid l bhō yath laṁ, ai iṇ ṁ ca s apn n mada śanaṁ, su hēna ca p atibōdhanaṁ, tamūt apu īṣ a ētas ṁ mu tiḥ, sa ai manōbuddhīn d iy ṇ ṁ c y pattiriti||89|| Achrya Charaka, Charaka Samhita, Niryan a Sagar press third edition 1941: Ch. Vi. 8/94 “pa ī ṣēta p a titaśca, i titaśca, s ataśca, saṁhananataśca, p am ṇataśca, s tmyataśca, satt ataśca, h aśa titaśca, v y y maśa titaśca, ayastaścēti, balap am ṇa iśēṣagrahaṇahētōḥ||94|| Achrya Charaka, Charaka Samhita, Niryana Sagar press third edition. 1941: Ch. Vi. 8/94 “tasyōpalabdhi nid napū a ūpaliṅgōpaśayasamp ptitaḥ||6|| Achrya Madhavakar, Madhav Nidan, Niryana Sagar press third edition. 1939: Ma. Ni. 1/4 nid naṁ pū a ūp -ṇi ūp ṇyupaśayastath | samp ptiścēti ijñ naṁ ōg ṇ ṁ pañcadh sm tam ||4|| Juyal RC, Negi S, Wakhode P, Bhat S, Bhat B, et al. Potential of Ayurgenomics Approach in Complex Trait Research: Leads from a Pilot Study on Rheumatoid Arthritis. PLoS ONE.2012; 7(9): e45752. doi:10.1371/journal.pone.0045752.

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Research & Reviews: A Journal of Drug Design & Discovery Volume 1, Issue 1 www.stmjournals.com

Synthesis and Anti-Bacterial Activity Profile of Cyclized Diazonium Compounds Priti Jain*, L. Naga Rajiv, Hemant R. Jadhav Department of Pharmacy, Birla Institute of Technology and Sciences, Pilani, Rajasthan, India Abstract Synthesis of cyclised diazonium compounds and their in vitro activity against various microorganisms is described. Several primary aromatic amines were diazotised and the resulting diazotised compounds were coupled with active methylene compounds to give hydrazono derivatives. These were cyclized with hydrazine hydrate, phenyl hydrazine, urea and o-phenylene diamine to give pyrazolin-5-one, substituted pyrazolin-5-ones, pyrimidin-di-ones and benzodiazepinone derivatives, respectively. Some hydrazine derivatives were also produced by reduction of diazo compounds with Sn/HCl. The synthesized compounds were assessed for their antimicrobial profile against Escherichia coli, Staphylococcus aureus, Bacillus cereus and Pseudomonas putida. Chloramphenicol and tetracycline were used as standards for the comparison of activity. Some of the compounds were found to exhibit promising antibacterial activity.

Keywords: diazotization, pyrazolinone, pyrimidinone, benzodiazepine, antimicrobial *Author for Correspondence E-mail: jain1199@gmail.com

INTRODUCTION Heterocyclic compounds hold a special place among pharmaceutically important natural and synthetic materials. The remarkable ability of heterocyclic nuclei to serve both as biomimetics and active pharmacophores has largely contributed to their unique value as traditional key elements of numerous drugs. Five or six membered ring compounds are ranked high among various classes of organic compounds in respect to the diverse biological activities. Pyrazolinone is a five membered lactam ring compound containing two nitrogens and ketone in the same molecule. Lactams are reported to have varying pharmacological activity. Some pyrazolinones are nonsteroidal anti-inflammatory agents used in the treatment of arthritis and other musculoskeletal and joint disorders. They also possess activities like antibacterial, antifungal, anti-inflammatory [1], antidiabetic, analgesic, antipyretic, antiviral and antineoplastic activity [2]. Pyrimidine ring structures also have received significant attention owing to their diverse range of biological properties. Pyrimidine nucleus is present in compounds used

clinically such as antibacterial agents, anticancer agent, antiviral agents, antifungal agents and antimalarial agents. Several important sulfonamide drugs are pyrimidine derivatives namely sulfadiazine, sulfamerazine and sulfadimidine. The nucleus also is an integral part of DNA and RNA, hence serves as an important part of nucleoside antibiotics, antibacterials and cardiovascular agents [3â&#x20AC;&#x201C; 5]. The benzodiazepine nucleus is also a wellstudied traditional pharmacophoric scaffold that has emerged as a core structural unit of various sedative-hypnotics, muscle relaxants, anxiolytics, antistaminic and anticonvulsant agents. Therefore diversely substituted benzodiazepine nuclei can serve as synthons for developing new drugs [6]. Keeping these facts in mind, we synthesized pyrazolin-5-one, substituted pyrazolin-5-ones, pyrimidin-diones and benzodiazepinone derivatives for probable antibacterial activity.

EXPERIMENTAL General: Melting points were determined on Buchi-530 melting point apparatus and are reported uncorrected. IR spectra were recorded on a

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Synthesis and Anti-Bacterial Activity Profile

Shimadzu-Prestige-21 FTIR and NMR on Bruker-400 MHz. All analytical samples were observed by thin layer chromatography, which was performed on EM Silica gel 60 F254 sheets (0.2 mm) using suitable solvent system. The spots were detected with a model UV lamp. Diazotization of Primary Aromatic Amines A mixture of aromatic amine (0.01 mole) in concentrated HCl (5 ml) was cooled to 0 - 5oC under ice. Cooled sodium nitrite solution (1.5 g in 10 mL of water) was added to it dropwise over 10 minutes. Addition of the solution was continued till the reaction mixture gives end point when tested with starch –iodide paper. General Procedure for the Preparation of Hydrazono Derivatives (C) The diazonium salt formed was then reacted with ethyl acetoacetate, which serves as a source of active methylene group (Figure 1). This proton of methylene group is very active and can replace anion from other compounds. Other compounds like ethyl malonate, ethyl acetone, ethyl cyanoacetate can also be used as a source of active methylene group.

PROCEDURE To the diazotized compound, the cooled mixture of active methylene compound formed from ethyl acetoacetate (0.01 M) and sodium acetate (0.05 M) in ethanol (50 ml) was added drop-wise with stirring for about 15 minutes. The reaction mixture was left for 2 hours at room temperature. Recrystallization was done using suitable solvent [7]. Preparation of Pyrazoline-5-one Derivatives (D1-D8) To compound ‘C1 to C8’ was added equimolar

Jain et al.

Solution of hydrazine hydrate and 20 ml ethanol. The mixture was then refluxed for about 4 hours. The completion of reaction was monitored by TLC using suitable solvent system. The final product was recrystallised using ethanol [8, 10]. Preparation of 2-Phenyl Pyrazole-3-one Derivatives (E1-E8) 30mL of glacial acetic acid was added to ‘C1 to C8’ and stirred. To the resulting solution was added equimolar quantity of phenyl hydrazine and anhydrous sodium acetate. It was then refluxed for about 5 hours. The reaction mixture was poured in ice cool water and stored in refrigerator overnight. Filtered and recrystallized with suitable solvent [8, 10]. Preparation of Substituted 2, 4-Pyrimidinedione Derivatives (F1-F8) To compound ‘C1 to C8’ was added equimolar solution of urea and 40 ml ethanol. The mixture was then refluxed for about 3-4 hours. The completion of reaction was monitored by TLC using suitable solvent system. On completion of reaction, the mixture was cooled under ice and kept for about one hour. The final product was recrystallised using ethanol [9, 10]. Preparation of Substituted Benzodiazepine Derivatives (G1-G8) To compounds ‘C1 to C8’ was added about 6 ml glacial acetic acid. Half molar of ophenylene diamine was taken and dissolved in minimum quantity of glacial acetic acid. Both solutions were mixed and refluxed for about 6 hours, cooled and kept overnight. It was then filtered and recrystallized using acetic acid [11].

Fig. 1: Reaction of Diazonium Compounds with ethylacetoacetate.

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Research & Reviews: A Journal of Drug Design & Discovery Volume 1, Issue 1

nutrient broth to prepare agar media. The solution was autoclaved at 121°C, 15psi for 15 minutes. The broth was then inoculated with culture as per USP guidelines and incubated for 15-18 hours at 37°C. 2% of agar powder was added to the nutrient broth to prepare agar media. Agar plates were prepared and wells were made in it for solvent, standard drug and for different concentrations (200 µg/ ml and 150 µg/ ml) of synthesized compounds. These were incubated at 37°C and zone of inhibition in cm was recorded after 12 hours. The experiments were performed in triplicate and average of the data is recorded in table 1 and synthesis of cyclized and reduced diazonium compounds is shown in Figure 2.

Preparation of Hydrazine Derivatives (H1H8) To stannous chloride (2.1 gm), 2 ml HCl was added and cooled. This solution was slowly added to diazonium salt solution. It was kept for 2-3 hours, filtered and recrystallized. Antimicrobial Screening The synthesized compounds were screened for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, Bacillus cerius and Pseudomonas putida by well plate method. The nutrient broth was prepared by dissolving 25 gm of Laurea Bertanni (LB) broth in 1000 ml of distilled water in a conical flask. 2% of agar powder was added to the

Drug code

Table 1: Activity Profile of Synthesized Compounds. Zone of inhibition in cm E.coli

B. cerius

S.aureus

P. putida

Standard drug

2.5

3.0

2.5

2.0

0.4

2.1

Inactive

1.1

Inactive

0.8

Inactive

1.9

Inactive

1.8

3.0

2.8

1.9

2.2

Inactive

2 .0

Inactive

1.7

0.3

2.5

Inactive

2.1

Inactive

1.2

2.2

Inactive

1.2

1.9

Inactive

2.5

0.6

Inactive

1.1

Inactive

1.5

Inactive

2.5

Inactive

1.8

Inactive

1.6

0.2

1.9

0.8

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Synthesis and Anti-Bacterial Activity Profile

Jain et al.

Fig. 2: Reaction Scheme Showing Synthesis of Cyclized and Reduced Diazonium Compounds. Table 2: Yield and Melting Points (in degrees celcius) of Synthesized Compounds. S. No

2-OCH3

3-Cl

4-Cl

4-CH3

3-CH3

4-OCH3

3-OCH3

180

215

200

180

187

178

120

132

170

148

152

121

153

72.5

142

101

160

162

62.5

22.3

82.7

127

123

110

94.8

120

160

180

120

178

151

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Research & Reviews: A Journal of Drug Design & Discovery Volume 1, Issue 1

RESULTS AND DISCUSSION All compounds synthesized were characterized using melting point, infrared, 1H-NMR and mass spectroscopy.The yield and melting point of all the compounds is reported in table 2. D1:5-Methyl-4-(phenyl-hydrazono)-2,4dihydro-pyrazole-3-one: IR data: 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 1650-1690 cm-1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching) NMR: 0.9δ (CH3), 6.2-7.0δ5 (Aromatic protons), 5.6 δ (N-H protons), m/z:201.31 D2:4-[(2-methoxy-phenyl)-hydrazono]5methyl-2,4-dihydro-pyrazole-3-one: IR data: 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 2818 (C-H stretching of CH3), 1650-1690 cm1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching), 1150 cm-1 (C-O stretching), m/z:232.13 NMR: 0.9δ (CH3), 6.3-6.5 δ (Aromatic protons), 6 δ (N-H protons), 3.73δ (OCH3) D3:4-[3-Chloro-phenyl)-hydrazono]5methyl-2,4-dihydro-pyrazole-3-one: IR data: 3380-3400 cm-1 (N-H stretching), 2950-3120 cm-1 (Aromatic C-H stretching), 1650-1690 cm-1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching) NMR: 0.9 δ (CH3), 6.3-6.7 δ (aromatic protons), 6δ (N-H protons), m/z 236.08 D4:4-[4-Chloro-phenyl)-hydrazono]5methyl-2,4-dihydro-pyrazole-3-one: IR data: 3380-3400 cm-1 (N-H stretching), 2950-3120 cm-1 (Aromatic C-H stretching), 1650-1690 cm-1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching) NMR: 0.9δ (CH3), 6.4-7.2 δ (aromatic protons), 6.2 δ (N-H protons), m/z 236.08 D5:4-[4-methyl-phenyl)-hydrazono]5methyl-2,4-dihydro-pyrazole-3-one: IR data: 3380-3400 cm-1 (N-H stretching), 2950-3120 cm-1 (Aromatic C-H stretching), 2750 cm-1 (C-H stretching), 1650-1690 cm-1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching)

NMR:0.9 δ (CH3), 2.34 δ (CH3 of phenyl), 6.3-6.8δ (aromatic protons), 6δ (N-H protons), m/z 216.13 D6:4-[3-Chloro-pheny)l-hydrazono]5methyl-2,4-dihydro-pyrazole-3-one: IR data: 3380-3400 cm-1 (N-H stretching), 2950-3120 cm-1 (Aromatic C-H stretching), 1650-1690 cm-1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching) NMR: 0.9δ (CH3), 2.34 δ (CH3 of phenyl), 6.2-6.8δ (aromatic protons), 6 δ (N-H protons) D7:4-[4-methoxy-pheny)l-hydrazono]5methyl-2,4-dihydro-pyrazole-3-one: IR data: : 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 2818 (C-H stretching of CH3), 1650-1690 cm1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching), 1150 cm-1 (C-O stretching) NMR: 0.9δ (CH3), 3.78 δ (OCH3 of phenyl), 6.2-6.8δ (aromatic protons), 6δ (N-H protons), m/z:232.13 D8:4-[3-methoxy-pheny)l-hydrazono]5methyl-2,4-dihydro-pyrazole-3-one: IR data: : 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 2818 (C-H stretching of CH3), 1650-1690 cm1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching), 1150 cm-1 (C-O stretching) NMR: 0.9 δ (CH3), 3.75δ (OCH3 of phenyl), 6.2-6.8δ (aromatic protons), 5.6 δ (N-H protons), m/z:232.13 E1: 5-methyl-2-phenyl-4[phenylhydrazono]- 2,4-dihydro-pyrazole-3-one: IR data: 3458 cm-1 (N-H stretching), 29003100 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching). NMR: 0.9δ (CH3 protons)6.2-6.8, 7.0-7.3 δ (Aromatic protons), 6.8δ (NH) E2:4[(2-methoxy-phenyl)-hydrazono]- 5methyl-2-phenyl-2,4-dihydro-pyrazole-3one: IR data: 3345 cm-1 (N-H stretching), 29003100 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1

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(C=N stretching), 1565-1450 cm-1 (C=C stretching), 1150 cm-1 (C-O stretching) NMR: 0.9 δ (CH3 protons), 3.73δ (OCH3), 6.2-6.5, 7.0-7.6δ (Aromatic protons), 6.9δ (NH), m/z=308.13

(C=N stretching), 1565-1450 cm-1 (C=C stretching), 1150 cm-1 (C-O stretching) NMR: 0.9δ (CH3 protons), 3.73 δ (OCH3),6.2-6.5, 7.0-7.6δ (Aromatic protons), 6.8 δ (NH), m/z=308.13

E3:4-[3-chloro-phenyl)-hydrazono]-5methyl-2-phenyl-2,4-dihydro-pyrazole-3one: IR data: 3455 cm-1 (N-H stretching), 29303120 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1 (C=N stretching), 1565-1450 cm-1 (C=C stretching), NMR: 0.9δ (CH3 protons), 6.26.5, 7.0-7.6δ (Aromatic protons), 7.0δ (NH), m/z=312.08

E8:4[(3-methoxy-phenyl)-hydrazono]-5methyl-2-phenyl-2,4-dihydro-pyrazole-3one: IR data: 3345 cm-1 (N-H stretching), 29003100 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1 (C=N stretching), 1565-1450 cm-1 (C=C stretching), 1150 cm-1 (C-O stretching) NMR: 0.9δ (CH3 protons), 3.73δ (OCH3),6.2-6.5, 7.0-7.6δ (Aromatic protons), 6.84δ (NH), m/z=308.13

E4:4-[(4-chloro-phenyl)-hydrazono]- 5methyl-2-phenyl-2,4-dihydro-pyrazole-3one: IR data: 3455 cm-1 (N-H stretching), 29303120 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1 (C=N stretching), 1565-1450 cm-1 (C=C stretching) NMR: 0.9 δ (CH3 protons), 3.73δ (OCH3),6.2-6.5, 7.0-7.6 δ (Aromatic protons), 6.8δ (NH), m/z=312.08 E5: 5-methyl-2-phenyl-4[p-tolylhydrazono]-2, 4-dihydro-pyrazole-3-one: IR data: 3425 cm-1 (N-H stretching), 29303320 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1 (C=N stretching), 1565-1450 cm-1 (C=C stretching), 2850 cm- (C-H stretching) NMR: 0.9, 2.35δ (CH3 protons), 6.3-6.81, 7.0-7.64δ (Aromatic protons), 6.8δ (NH), m/z=292.13 E6:5-methyl-2-phenyl-4[m-tolylhydrazono]-2,4-dihydro-pyrazole-3-one: IR data: 3425 cm-1 (N-H stretching), 29303320 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1 (C=N stretching), 1565-1450 cm-1 (C=C stretching), 2850 cm- (C-H stretching) NMR: 0.9,2.35δ (CH3 protons)6.2-6.8, 7.0-7. δ3 (Aromatic protons), 6.8δ (NH), m/z=292.13 E7:4[(4-methoxy-phenyl)-hydrazono]-5methyl-2-phenyl-2,4-dihydro-pyrazole-3one: IR data: 3345 cm-1 (N-H stretching), 29003100 cm-1 (Aromatic C-H stretching), 16701690 cm-1(C=O stretching), 1600-1700 cm-1

F1:6-methyl-5(phenyl-hydrazono)-5-Hpyridine-2, 4-dione: IR data: 3424 cm-1 (N-H stretching), 3052 cm-1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (N-N=C stretching) NMR: 0.9δ (CH3), 7, 10 δ (NH protons), 6.4-7.01δ (Aromatic protons), m/z=230.22 F2:5[(2-methoxy-phenyl)-hydrazono]-6methyl-5-H-pyridine-2, 4-dione: IR data: 3424 cm-1 (N-H stretching), 3052 cm-1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (N-N=C stretching), 1243 cm-1 (C-O stretching) NMR: 0.9 (CH3), 7, 10(NH protons), 6.3-6.51 (Aromatic protons), 3.5 (methoxy protons), m/z=260.09 F3:5[(3-chloro-phenyl)-hydrazono]-6methyl-5-H-pyridine-2, 4-dione: IR data: 3345 cm-1 (N-H stretching), 3153 cm1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (NN=C stretching) NMR: 0.9δ (CH3), 7.1, 10.2δ (NH protons), 6.3-6.6 δ (Aromatic protons), m/z=264.04

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Research & Reviews: A Journal of Drug Design & Discovery Volume 1, Issue 1

F4:5[(4-chloro-phenyl)-hydrazono]-6methyl-5-H-pyridine-2, 4-dione: IR data: 3345 cm-1 (N-H stretching), 3153 cm1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (NN=C stretching) NMR: 0.9δ (CH3), 7, 10 δ (NH protons), 6.3-6.6δ (Aromatic protons), m/z=264.04 F5:6-methyl-5-(p-tolyl-hydrazano)-5-Hpyridine-2, 4-dione: IR data: 3347 cm-1 (N-H stretching), 3157 cm1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (NN=C stretching) NMR: 0.9, 2.3δ (CH3), 7, 10 δ (NH protons), 6.3-6.6δ (Aromatic protons), m/z=244.10 F6:6-methyl-5-(m-tolyl-hydrazano)-5-Hpyridine-2, 4-dione: IR data: 3347 cm-1 (N-H stretching), 3157 cm1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (NN=C stretching) NMR: 0.9, 2.3δ (CH3), 7, 10 δ (NH protons), 6.3-6.6δ (Aromatic protons), m/z=244.10 F7:5[(4-methoxy-phenyl)-hydrazono]-6methyl-5-H-pyridine-2, 4-dione: IR data: 3424 cm-1 (N-H stretching), 3052 cm-1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (N-N=C stretching), 1243 cm-1 (C-O stretching) NMR: 0.9δ (CH3), 7, 10 δ (NH protons), 6.3-6.51δ (Aromatic protons), 3.5δ (methoxy protons), m/z=260.09 F8:5[(3-methoxy-phenyl)-hydrazono]-6methyl-5-H-pyridine-2, 4-dione: IR data: 3424 cm-1 (N-H stretching), 3052 cm-1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (N-N=C stretching), 1243 cm-1 (C-O

stretching) NMR: 0.9δ (CH3), 7, 10δ (NH protons), 6.3-6.51δ (Aromatic protons), 3.5δ (methoxy protons), m/z=260.09 G1:4-methyl-3(-phenyl-hydrazono)-1,3dihydro-benzo-1,4-diazepin-2-one: IR data: 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 2818 (C-H stretching of CH3), 1650-1690 cm1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching) NMR: 0.9δ (CH3), 3.1δ (CH2), 4, 7δ (NH protons), 6.4-7.01δ (Aromatic protons), m/z=264.14 G2:3[(2-methoxy-phenyl)-hydrazono]-4methyl-,3-dihydro-benzo-1,4-diazepin-2one: IR data: 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 2818 (C-H stretching of CH3), 1650-1690 cm1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching), 1280 cm-1 (C-O stretching) NMR: 0.9δ (CH3), 3,2 δ (CH2), 3.9δ (methoxy protons), 4, 7δ (NH protons), 6.4-7.6δ (Aromatic protons), m/z=308.13 G3:3[(3-chloro-phenyl)-hydrazono]-4methyl-,3-dihydro-benzo-1,4-diazepin-2one: IR data: 3424 cm-1 (N-H stretching), 3052 cm-1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (N-N=C stretching) NMR: 0.9δ (CH3), 3,2 δ (CH2), 3.9 δ (methoxy protons), 4, 7 δ (NH protons), 6.4-8δ (Aromatic protons), m/z=312.08

G4:3[(4-chloro-phenyl)-hydrazono]-4methyl-,3-dihydro-benzo-1,4-diazepin-2one: IR data: 3424 cm-1 (N-H stretching), 3052 cm-1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (N-N=C stretching) NMR: 0.9δ (CH3), 3,2δ (CH2), 3.9δ (methoxy protons), 4, 7 δ (NH

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Synthesis and Anti-Bacterial Activity Profile

protons), 6.4-8δ m/z=312.08

(Aromatic

protons),

G5:4-methyl-3(-p-tolyl-hydrazono)-1,3dihydro-benzo-1,4-diazepin-2-one: IR data: 3345 cm-1 (N-H stretching), 3153 cm1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (NN=C stretching) NMR: 0.9 , 2.35 δ (CH3), 3.2δ (CH2), 3.9 δ (methoxy protons), 4, 8δ (NH protons), 6.4-7.6 δ (Aromatic protons), m/z=292.13 G6:4-methyl-3(-m-tolyl-hydrazono)-1,3dihydro-benzo-1,4-diazepin-2-one: IR data: 3345 cm-1 (N-H stretching), 3153 cm1 (Aromatic C-H stretching), 2800- 2900 cm-1 (aliphatic C-H stretching), 1688, 1676 cm-1 (C=O stretching), 1592 cm-1, 1565 cm-1, 1481 cm-1 (C=N, C=C stretching), 1284 cm-1 (NN=C stretching) NMR: 0.9 , 2.35δ (CH3), 3.2δ (CH2), 3.9δ (methoxy protons), 3.8, 7.5 δ (NH protons), 6.4-7.6δ (Aromatic protons), m/z=292.13 G7:3[(4-methoxy-phenyl)-hydrazono]-4methyl-,3-dihydro-benzo-1,4-diazepin-2one: IR data: 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 2818 (C-H stretching of CH3), 1650-1690 cm-1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching), 1280 cm-1 (C-O stretching) NMR: 0.9δ (CH3), 3,2δ (CH2), 3.9δ (methoxy protons), 4, 8δ (NH protons), 6.4-7.6δ (Aromatic protons), m/z=308.13 G8:3[(3-methoxy-phenyl)-hydrazono]-4methyl-,3-dihydro-benzo-1,4-diazepin-2one: IR data: 3400-3600 cm-1 (N-H stretching), 2900-3100 cm-1 (Aromatic C-H stretching), 2818 (C-H stretching of CH3), 1650-1690 cm1 (C=O stretching), 1600-1700 cm-1 (C=N stretching), 1580-1450 cm-1 (C=C stretching), 1280 cm-1 (C-O stretching) NMR :0.9δ (CH3), 3.2δ (CH2), 3.9δ (methoxy protons), 4, 8 δ (NH protons), 6.4-7.5δ (Aromatic protons), m/z=308.13

Jain et al.

H1:phenyl hydrazine: IR data: 3000-3100 cm-1 (aromatic C-H stretching), 3400-3500cm-1(N-H stretching), NMR: 2,4 δ (NH2, NH proton), 6.6-7.18δ (Aromatic protons), m/z : 108.07 H2:2-methoxy phenyl hydrazine: IR data: 3000-3100 cm-1 (aromatic C-H stretching), 3400-3500cm-1(N-H stretching), 2856 cm-1 (C-H stretching of methoxy), 1150 cm-1 (C-O stretching) NMR: 2,4 δ (NH2, NH proton), 3.5 δ (methoxy protons), 6.8-7.38δ (Aromatic protons), m/z : 138.08 H3:3-chloro-phenyl hydrazine: IR data: 3000-3240 cm-1 (aromatic C-H stretching), 3380-3500cm-1(N-H stretching) NMR: 2.3,4.1 δ (NH2, NH proton), 6.6-7.18δ (Aromatic protons), m/z : 142.03 H4:4- chloro-phenyl hydrazine: IR data: 3000-3240 cm-1 (aromatic C-H stretching), 3380-3500cm-1(N-H stretching) NMR: 2.3,4.1 δ (NH2, NH proton), 6.6-7.18δ (Aromatic protons), m/z : 142.03 H5:4-methyl-phenyl hydrazine: IR data: 3000-3100 cm-1 (aromatic C-H stretching), 3400-3500cm-1(N-H stretching), 2856 cm-1 (C-H stretching of methyl) NMR: 2.6,4 δ (NH2, NH proton), 2.35 δ (methyl protons), 6.7-7.58δ (Aromatic protons), m/z : 122.17 H6:3- methyl-phenyl hydrazine: IR data: 3000-3100 cm-1 (aromatic C-H stretching), 3400-3500cm-1(N-H stretching), 2856 cm-1 (C-H stretching of methyl) NMR: 2,4 δ (NH2, NH proton), 2.35 δ (methyl protons), 6.6-7.18δ (Aromatic protons), m/z : 122.17 H7:4-methoxy phenyl hydrazine: IR data: 3000-3100 cm-1 (aromatic C-H stretching), 3400-3500cm-1(N-H stretching), 2856 cm-1 (C-H stretching of methoxy), 1150 cm-1 (C-O stretching) NMR: 2,4 δ (NH2, NH proton), 3.5 δ (methoxy protons), 6.6-7.18δ (Aromatic protons), m/z : 138.08 H8: 3-methoxy phenyl hydrazine: IR data: 3000-3100 cm-1 (aromatic C-H stretching), 3400-3500cm-1(N-H stretching),

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2856 cm-1 (C-H stretching of methoxy), 1150 cm-1 (C-O stretching) NMR: 2,4 δ (NH2, NH proton), 3.5 δ (methoxy protons), 6.6-7.18δ (Aromatic protons), m/z : 138.08

CONCLUSION Various cyclized diazonium compounds were synthesized possessing different heterocyclic ring systems in good yield. The well plate method for antibacterial activity showed significant reduction in bacterial growth in terms of zone of inhibition around the well. Chloramphenicol and tetracycline were used as standard drugs for the comparison. It was observed that phenyl group bearing no substituent, was inactive against E.coli and S. aureus. Benzodiazepine derivatives and reduced compounds displayed comparable activity to standard against all tested strains of micro-organisms.

REFERENCES 1. Bekhit AA, Ashour HMA , Ghany YSA., Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur J Med Chem 2008; 43: 456–63p. 2. Chauhan A, Sharma PK, Kaushik N., Pyrazole: a versatile moiety. Inter J Chem Tech Res 2011; 3: 11–7p. 3. Amir M, Javed SA, Kumar H., Pyrimidine as anti-inflammatory agent: A review. IJPS 2007; 69: 337–43p.

4. Ahluwalia VK, Chandra RJ. A convenient synthesis of novel pyrimidine analogues of o- hydroxy chalcones and pyrano [2, 3-d] pyrimidines and their biological activities. J Chem Res 2000; 4:162–3p. 5. El-Bendary, Badria FA. Synthesis, DNAbinding and Antiviral Activity of Certain Pyrazolo [3, 4-d] pyrimidine Derivatives. Arch Pharm. 2000; 99:333–8p. 6. Santagada V, Perissutti E, Fiorino F. Microwave enhanced synthesis of 1, 4benzodiazepine-2- one. Tetrahedron Lett 2001; 42: 2397–400p. 7. A.I. Vogel, Practical Organic Chemistry, edn. 3, 1967; 442. 8. Das N, Verma A., Synthesis and biological evaluation of some new aryl pyrazole-3one derivatives as potential hypoglycemic agents. Indian J of chem. 2008; 47B: 1555–8p. 9. Fayed AA, Hosni HM, Synthesis and pharmacological activity of some new thieno [2,3- d] pyrimidine and pyrimidopyrazolothienopyrimidine derivatives. World J of Chem. 2009; 4–1: 58–65p. 10. Saleh MA, Abdel MF., Synthesis of Novel 3H-Quinazolin-4-ones Containing Pyrazolinone, Pyrazole and Pyrimidinone Moieties Molecules. 2003; 8: 363–6p. 11. Narule M, Meshram J, Santhakumari B , Shanware. Synthesis of 2-[4-(10Hsubstituted phenothiazine-3- yl)-6pyrimidin-2-phenylthiol/ol/amine/thiol] pyrroles. E-J. of Chem. 2007; 4: 53–9p.

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Targeting Cancer through Angiogenesis Inhibition: Prospective of Azole Based Small Molecules Pratap Chandra Acharya* Department of Pharmaceutical Chemistry, SPPSPTM, SVKM'S NMIMS University, Mumbai, India Abstract Anticancer drug discovery is a major focus area in the pharmaceutical industry and obtaining targeted drug molecules for the malignant tissue is a major hurdle in this process. With the advancement in the knowledge of biological targets, cancer specific molecules such as monoclonal antibodies have been designed and produced in the recent past. However, the cost and effectiveness of these special products are the biggest challenges for cancer treatment. Small molecules are considered as the best chemotherapeutic intervention to treat cancer at the present time. This article describes the possibility of azole based small molecules as inhibitor of tumor angiogenesis, which can be explored for anticancer drug discovery.

Keywords: Angiogenesis, Anticancer Drugs, Monoclonal Antibodies, Azoles, Small Molecules, HUVEC Assay