SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL OXADIAZOLE DERIVATIVES

SYNOPSIS FOR M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

BY

SATISH KUMAR SINGH

I M.PHARM (2009-2010) PHARMACEUTICAL CHEMISTRY DEPARTMENT OF PHARMACEUTICAL CHEMISTRY M.S. RAMAIAH COLLEGE OF PHARMACY BANGALORE-560054.

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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. NAME OF THE SATISH KUMAR SINGH CANDIDATE AND Q.NO.- 63, STREET- 01, SECTOR- 9’A’, ADDRESS BOKARO STEEL CITY, JHARKHAND-827009

M.S.RAMAIAH COLLEGE OF PHARMACY, 2. NAME OF M.S.R.I.T. POST, INSTITUTION M.S.R. NAGAR, BANGALORE-560054

3. COURSE OF THE M.PHARM PHARMACEUTICAL CHEMISTRY STUDY AND SUBJECT

TH 4. DATE OF ADMISSION 11 JUNE 2009.

SYNTHESIS AND BIOLOGICAL 5. TITLE OF THE TOPIC EVALUATION OF SOME NOVEL OXADIAZOLE DERIVATIVES.

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6. BRIEF RESUME OF THE INTENDED WORK

6.1 NEED FOR THE STUDY

2,5-Disubstituted 1,3,4-Oxadiazoles constitute an unique class of nitrogen and oxygen containing five membered heterocycles. They have been found to possess a wide variety of pharmacological activities1.

1,3,4-Oxadiazoles derivatives are known to exhibit important biological activities such as antibacterial, antioxidant, anticonvulsant, antimiotic, analgesic, anti-inflammatory, antiemetic, hypoglycemic, antimicrobial and antifungal activities2-11.

Benzimidazole derivatives are of wide interest because of their diverse biological activity and clinical applications. This ring system is present in numerous antiparasitic, fungicidal, anthelmintic and anti-inflammatory drugs24.

Due to their wide range of applications, these compounds have received a great deal of attention in connection with their synthesis and we intend to synthesize some novel derivatives of oxadiazoles with heterocycles like benzimidazoles and evaluate their biological activity.

3 6.2. REVIEW OF LITERATURE

 Synthesis of 2,5- disubsitued 1,3,4- Oxadiazoles as biologically active heterocycles were reported1.

 Synthesis of some new 1,3,4- oxadiazoles as antimicrobial agents were reported 2.

 Microwave assisted synthesis of some 5-phenyl-2-[(N-substituted phenyl) thioacetamido]-1,3,4-oxadiazoles as antibacterial and antioxidant agents were reported 3.

 Synthesis of oxadiazolylindole derivatives and their antiinflammatory activity were reported 4.

 Synthesis and biological evaluation of 2-[3-(4-methoxyphenyl)propan-3- one]-5-(substituted phenyl)-1,3,4-oxadiazoles were reported 5.

 Synthesis of some new 2,5-disubstituted 1,3,4-oxadiazole derivatives and their antiinflammatory activity were reported 6.

 Synthesis of new fungitoxic 2-aryl-1,3,4-oxadiazolo[3,2-a]-s-triazine-5,7- dithiones and their 6-aryl sulphonyl derivatives were reported 7.

 Synthesis and antimicrobial activity of some 2-(N-substituted carboxamidomethyl/ethylthio)-5-(2’-thienyl)-1,3,4-oxadiazoles were reported 8.

 Synthesis and biological activity of some oxoimidazolines and oxadiazoles were reported 9.

 Synthesis and antimicrobial activity of 5’-aryl substituted-(4’’- benzylidene-4,5-dihydro-5-oxo-1-(H)-imidazolo)-1’’,3’’,4’’-oxadiazoles were reported 10.

 Synthesis of triazole, thiadiazole and oxadiazole bearing 2-thiomethyl benzimidazole and their biological evaluation were reported 11.

4  Synthesis and antibacterial activities of 1,3,4-oxadiazole and pyrazoline derivatives containing 1,8-naphthyridine moiety were reported 12.

 Synthesis and screening of 5-aryl-1,3,4-oxadiazole-2-thiocarboxylic acids for antibacterial activity were reported 13.

 Synthesis and antimicrobial activity of some new 1,8- naphthyridinylaminophenyl-1,3,4-oxadiazoles were reported 14.

 Synthesis of certain 1,3,4-oxadiazoles as potential antitubercular and antimicrobial agents were reported 15.

 Synthesis of 2-(3-nitronaphtho[2,1-b] furan-2-yl)-5-substituted-1,3,4- oxadiazoles and their biological activities were reported 16.

 Synthesis and antimicrobial activity of 1,3,4-oxadiazole incorporated benzoxazoles were reported 17.

 Synthesis and antimicrobial activity of some new 1-substituted-2-methyl- 3-ethoxycarbonyl-5-(1,2,3,4-tetrazolyl)/(1,3,4-oxadiazolyl)/(1,3,5- triazinyl) methoxy indoles were reported 18.

 Synthesis of 5-(1H-indazol-3-yl)-N-phenyl-1,3,4-oxadiazole-2-amine, 5- (1H-indazol-3-yl)-N-phenyl-1,3,4-thiadiazole-2-amine and 5-(1H-indazol- 3-yl)-4-phenyl-4H-1,2,4-trazol-3-thiol by conventional and non conventional methods was reported19.

 A convenient synthesis of 5-aryl-2-[p-(1,8-naphthyridine-2-yl) phenoxymethyl]-1,3,4-oxadiazoles under microwave irradiation were reported 20.

 Molecular sieves assisted synthesis of novel 3-chloromethyl-5-substituted pyridine-[1,2,4] oxadiazoles were reported 21.

 A facile synthesis of symmetrical and unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles were reported 22.

 Synthesis, antiprotozoal and antibacterial activity of nitro- and halogeno- substituted benzimidazole derivatives were reported23. 5  Synthesis and antimicrobial activity of N-substituted benzimidazoles were reported 24.

 Studies in naphthofurans: part III-synthesis of 2-substituted naphtho[2,1- b]furans, 2-(2’-aryl-3’-acetyl-1’,3’,4’-oxadiazolyl)aminonaphtho[2,1- b]furans and their biological activities were reported 25.

 Solid phase traceless synthesis of benzimidazoles with three combinatorial steps were reported 26.

 Solid phase synthesis of 1-alkyl-2-alkylthio-5’-carbamoylbenzimidazoles were reported 27.

 Alkylation studies on (1H-benzimidazole-2-yl)-acetic acid derivatives were reported 28.

 1-Aza-1’,3’-diaza-3,3’-sigmatropic rearrangements- A convenient synthesis of benzimidazole derivatives were reported 29.

 Relationship between structure of benzimidazole derivatives and selective virus inhibitory activity was discussed30.

 Synthesis and antimicrobial activity of some new benzimidazole derivatives were reported31.

6 6.3 OBJECTIVES OF STUDY

1) To synthesize the proposed derivatives with optimum yield.

2) To purify the synthesized compounds.

3) To characterize the synthesized compounds by spectral interpretation and by means of chemical tests.

4) To evaluate the biological activity of the synthesized compounds.

7. MATERIAL AND METHODS

7.1 SOURCE OF DATA

1) Chemical abstracts, Indian Journal of Chemistry, Indian Journal of Pharmaceutical Sciences, Tetrahedron Letters, Tetrahedron, Journal of Indian Chemical Society, Molecules.

2) Lab based studies.

7.2 METHODS OF COLLECTION OF DATA

PRE-LABORATORY AND LABORATORY WORK

1) PRE-LABORATORY WORK The chemicals & reagents required for the synthesis and evaluation of the proposed compounds will be procured from reputed chemical suppliers like Merck, Ranchem, Fischer Scientific and Himedia etc.

2) LABORATORY WORK A) SYNTHESIS Conventional methods of synthesis4-20 as well as microwave assisted synthesis3 will be attempted. The completion of the reaction will be

7 determined by TLC. Advantages and feasibility of the methods will be analysed.

B) PURIFICATION The synthesized compounds will be purified by different methods like fractional crystallization, recrystallization, distillation and chromatographic methods2.The purity will be ascertained by TLC.

C) CHARACTERIZATION The synthesized compounds will be characterized by: 1. Chemical tests for important functional groups. 2. Study of spectral data.

D) BIOLOGICAL STUDIES

1. SCREENING OF ANTIBACTERIAL ACTIVITY BY DISC DIFFUSION METHOD: This will be carried out on both Gram positive and Gram negative organisms like Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis etc using sterile Media like Mueller-Hinton Agar etc by Disc Diffusion Method. Zone of inhibition of the compounds synthesized will be noted and compared with that of standard drugs like Amoxicillin, Ciprofloxacin etc32.

2. SCREENING OF ANTIFUNGAL ACTIVITY BY DISC

DIFFUSION METHOD: This will be carried out on organisms like Candida albicans and Aspergillus niger using Media like Sabouraud Dextrose Agar. Zone of inhibition of the compounds synthesized will be compared with that of standard drugs like griseofulvin33. The entire work will be done using Horizontal Laminar Flow hood. 3. SCREENING FOR IN-VITRO ANTI INFLAMMATORY ACTIVITY: This will be carried out according to the procedure suggested by Mizushima, Elias and Rao34-35. 8 .

7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS?

"NOT APPLICABLE”

7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3?

"NOT APPLICABLE"

9 8. LIST OF REFERENCES

1 Kagthara PR, Shah NS, Doshi RK, Parekh HH. Synthesis of 2,5- disubsitued 1,3,4- Oxadiazoles as biologically active heterocycles. Indian J Chem 1999 May;38B:572-576. 2 Laddi UV, Desai SR, Bennur RS, Bennur SC. Synthesis of some new 1,3,4- oxadiazoles as antimicrobial agents. Indian J Heterocycl Chem 2002 April-June;11:319-322. 3 Rajasekaran S, Rao GK, Pai PNS and Vedavathy J. Microwave assisted synthesis of some 5-phenyl-2-[(N-substituted phenyl) thioacetamido]-1,3,4-oxadiazoles as antibacterial and antioxidant agents. Indian J Heterocycl Chem 2009 Jan-March;18:309-310. 4 Sonar VN, Yazadan SK, Sreenivasulu N. Synthesis of oxadiazolylindole derivatives and their antiinflammatory activity. Indian J Heterocycl Chem 2001 April-June;10:299-302. 5 Husain A, Alam MM, Zaman MS, Ahuja P. Synthesis and biological evaluation of 2-[3-(4-methoxyphenyl)propan-3-one]-5-(substituted phenyl)-1,3,4-oxadiazoles. Indian J Heterocycl Chem 2008 Jan- Mar;17:265-266. 6 Amir M, Kumar S. Synthesis of some new 2,5-disubstituted 1,3,4- oxadiazole derivatives and their antiinflammatory activity. Indian J Heterocycl Chem 2004 July-Sep;14:51-54. 7 Tripathi D, Mishra AR. Synthesis of new fungitoxic 2-aryl-1,3,4- oxadiazolo[3,2-a]-s-triazine-5,7-dithiones and their 6-aryl sulphonyl derivatives. Indian J Heterocycl Chem 2007 Jan-March;16:239-242. 8 Khazi IM, Koti RS. Synthesis and antimicrobial activity of some 2-(N- substituted carboxamidomethyl/ethylthio)-5-(2’-thienyl)-1,3,4- oxadiazoles. Indian J Heterocycl Chem 2003 July-Sep;13:87-88. 9 Patel KD, Mistry BD, Desai KR. Synthesis and biological activity of some oxoimidazolines and oxadiazoles. Indian J Heterocycl Chem 2001 July-Sept;11:63-66.

10 10 Rajpurohit S, Garg SP, Sah P. Synthesis and antimicrobial activity of 5’-aryl substituted-(4’’-benzylidene-4,5-dihydro-5-oxo-1-(H)- imidazolo)-1’’,3’’,4’’-oxadiazoles. Indian J Heterocycl Chem 2005 Oct-Dec;15:129-132. 11 Murugan V, Prasad KR, Sarma GVSR, Ramanathan M, Suresh B. Synthesis of triazole, thiadiazole and oxadiazole bearing 2-thiomethyl benzimidazole and their biological evaluation. Indian J Heterocycl Chem 2001 Oct-Dec;11:169-170. 12 Mogilaiah K, Sakram B. Synthesis and antibacterial activities of 1,3,4- oxadiazole and pyrazoline derivatives containing 1,8-naphthyridine moiety. Indian J Heterocycl Chem 2004 April-June;13:289-292. 13 Pathak DP, Jain N, Mishra P, Jain S. Synthesis and screening of 5-aryl- 1,3,4-oxadiazole-2-thiocarboxylic acids for antibacterial activity. Indian J Heterocycl Chem 2005 Oct-Dec;15:177-178. 14 Mogilaiah K, Sudhakar GR. Synthesis and antimicrobial activity of some new 1,8-naphthyridinylaminophenyl-1,3,4-oxadiazoles. Indian J Heterocycl Chem 2001 Oct-Dec;11:163-166. 15 Dhol SR, Bhimani AS, Khunt RC, Parikh AR. Synthesis of certain 1,3,4-oxadiazoles as potential antitubercular and antimicrobial agents. Indian J Heterocycl Chem 2005 July-Sep;15:63-64. 16 Rajashekhara H, Ramesh D, Chandrashekhar C, Mahadevan KM, Vaidya VP. Synthesis of 2-(3-nitronaphtho[2,1-b] furan-2-yl)-5- substituted-1,3,4-oxadiazoles and their biological activities. Indian J Heterocycl Chem 2007 April-June;16:353-356. 17 Basavaraja BM, Vagdevi HM, Srikrishna LP, Shubha BS, Vaidya VP. Synthesis and antimicrobial activity of 1,3,4-oxadiazole incorporated benzoxazoles. Indian J Heterocycl Chem 2008 July-Sept;18:05-08. 18 Bhovi MG, Gadaginamath GS, Megadi VB. Synthesis and antimicrobial activity of some new 1-substituted-2-methyl-3- ethoxycarbonyl-5-(1,2,3,4-tetrazolyl)/(1,3,4-oxadiazolyl)/(1,3,5-

11 triazinyl) methoxy indoles. Indian J Heterocycl Chem 2004 July- Sept;14:07-10.

19 More MS, Kale SB, Karale BK. Synthesis of 5-(1H-indazol-3-yl)-N- phenyl-1,3,4-oxadiazole-2-amine,5-(1H-indazol-3-yl)-N-phenyl-1,3,4- thiadiazole-2-amine and 5-(1H-indazol-3-yl)-4-phenyl-4H-1,2,4- trazol-3-thiol by conventional and non conventional methods. Indian J Heterocycl Chem 2006 Oct-Dec;16:155-158. 20 Mogilaiah K, Prashanthi M. A convenient synthesis of 5-aryl-2-[p- (1,8-naphthyridine-2-yl) phenoxymethyl]-1,3,4-oxadiazoles under microwave irradiation. Indian J Heterocycl Chem 2005 Jan-March; 14:185-188. 21 Bora RO, Jadhav GR, Kale RP, Dabhade SK, Gill CH, Farooqui M. Molecular sieves assisted synthesis of novel 3-chloromethyl-5- substituted pyridine-[1,2,4] oxadiazoles. Indian J Heterocycl Chem 2008 Oct-Dec;18:189-190. 22 Rani R, Makrandi JK. A facile synthesis of symmetrical and unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles. Indian J Heterocycl Chem 2008 July-Sept;18:81-82. 23 Kazimierczuk Z, Upcroft JA, Upcroft P, Gorska A, Starosciak B, Laudy A. Synthesis, antiprotozoal and antibacterial activity of nitro- and halogeno-substituted benzimidazole derivatives. Acta Biochimica Polonica;49;No.1/2002:185-195. 24 Jadhav SB, Shastri RA, Bagul KR, Gaikwad KV. Synthesis and antimicrobial activity of N-substituted benzimidazoles. Indian J Heterocycl Chem 2009 Jan-Mar;18:319-320. 25 Vagdevi HM, Vaidya VP. Studies in naphthofurans: part III-synthesis of 2-substituted naphtho[2,1-b]furans, 2-(2’-aryl-3’-acetyl-1’,3’,4’- oxadiazolyl)aminonaphtho[2,1-b]furans and their biological activities. Indian J Heterocycl Chem 2001 April-June;10:253-260. 26 Smith JM, Krcnak V. Solid phase traceless synthesis of benzimidazoles with three combinatorial steps. Tetrahedron 1999;40: 7633-7636.

12 27 Lee J, Gauthier D, Rivero RA. Solid phase synthesis of 1-alkyl-2- alkylthio-5’-carbamoylbenzimidazoles. Tetrahedron 1998;39:201-204.

28 Dubey PK, Reddy PVVP. Alkylation studies on (1H-benzimidazole- 2-yl)-acetic acid derivatives. Indian J Heterocyclic Chem 2006 Oct- Dec;16:131-134. 29 Carvalho MTVL, Lobo AM, Branco PS, Prabhakar S. 1-Aza-1’,3’- diaza-3,3’-sigmatropic rearrangements- A convenient synthesis of benzimidazole derivatives. Tetrahedron 1997;38:3115-3118. 30 Tamm I, Bablanian R, Nemes MM, Shunk CH, Robinson FM, Folkers K. Relationship between structure of benzimidazole derivatives and selective virus inhibitory activity. From The Rockefeller Institute, and the Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey. 1961 March 31: 625-656. 31 Masry AHE, Fahmy HH, Abdelwahed SHA. Synthesis and antimicrobial activity of some new benzimidazole derivatives. Molecules 2000;5:1429-1438. 32 Edwin HL, Alberbalows, William JH, Jean JR . Manual of Clinical Microbiology 1985, 4th Edition, American Society for Microbiology, Washington:250-255. 33 Hugo WB, Russel AD. Pharmaceutical Microbiology 1998, 6th Edition, Blackwell Science Ltd, London:237-251. 34 Mizushima Y. Inhibition of protein denaturation by antirheumatic or antiplogistic agents. Arch Int. Pharmacodyn 1964;149:1-7. 35 Elias G, Rao MNA. Inhibition of albumin denaturation and anti- inflammatory activity of dehydrozingerone and its analogs. Indian J Exp Boil 1988 July;26:540-542.

13 9. SIGNATURE OF CANDIDATE

10. REMARKS OF THE GUIDE

11. NAME AND DESIGNATION OF

11.1 GUIDE Mrs. JUDY JAYS ASST. PROFESSOR Department of Pharmaceutical chemistry M.S. Ramaiah college of pharmacy Bangalore-560054. 11.2 SIGNATURE

11.3 CO-GUIDE Not Applicable

11.4 SIGNATURE Not Applicable

11.5 HEAD OF THE PROF. C.H.S. VENKATARAMANA DEPARTMENT Department of Pharmaceutical Chemistry M.S. Ramaiah college of pharmacy (IN CHARGE) Bangalore-560054.

11.6 SIGNATURE

12. REMARKS OF THE PRINCIPAL

12.1 SIGNATURE

14 15