Synthesis and Evaluation of Some New Fexofenadine Derivatives

SYNTHESIS AND BIOLOGICAL EVALUATION OF

SOME NEW OXADIAZOLE ANALOGUES

PROTOCOL FOR M.PHARM DISSERTATION

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

BY KULKARNI VIVEK SHAMSUNDAR, B.Pharm., DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, 2008-2009.

UNDER THE GUIDANCE OF

Dr. SENTHIL KUMAR G.P., M Pharm., PhD., PROFESSOR AND HEAD, DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, BHARATHI COLLEGE OF PHARMACY, BHARATHI NAGARA. KARNATAKA-571422

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE ,KARNATAKA

ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. Name of the Candidate and Address PRESENT ADDRESS: KULKARNI VIVEK SHAMSUNDAR, I M. Pharm., DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, C/O BHARATHI COLLEGE OF PHARMACY, BHARATHI NAGARA, MANDYA (DIST), KARNATAKA-571422. 2. Name of the Institution BHARATHI COLLEGE OF PHARMACY BHARATHI NAGARA, MANDYA. 571422 3. Course of Study and Subject MASTER OF PHARMACY IN PHARMACEUTICAL CHEMISTRY.

4. Date of Admission of Course 30-06-2008 5. Title of Topic SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NEW OXADIAZOLE ANALOGUES

6. Brief Resume of the Intended Work 6.1 Need for the study 6.2 Review of the literature ENCLOSURE-I 6.3 Objectives of the study

7 Materials and Methods 7.1 Source of data 7.2 Method of collection of data 7.3 Does study require any investigations or ENCLOSURE-II interventions to conducted on patients or other human or animal? If so, please describe briefly. 7.4 Has ethical clearance been obtained from your institution in case of 7.3

8 List of References ENCLOSURE-III

9. Signature of the candidate: (Kulkarni Vivek)

10. Remarks of the guide: This work can be carry out in our lab

11. 11.1 Name And Designation of Guide: Dr. Senthil Kumar G.P. Professor and Head of Department Pharmaceutical Chemistry, Bharathi College Of Pharmacy, Bharathinagar. 571 422

11.2 Signature

11.3 Co-Guide ----

11.4 Signature

11.5 Head of the department Dr. Senthil Kumar G.P. Professor and Head of Department Pharmaceutical Chemistry, Bharathi College Of Pharmacy, Bharathinagar. 571 422

11.6 Signature

12. 12.1 Remarks of the Chairman and Principal:

Forwarded For Approval Dr. T. TAMIZH MANI. Principal, Bharathi College Of Pharmacy, Bhrathinagara 571 422

12.2 Signature

ENCLOSURE-I

6. BRIEF RESUME OF INTENDED WORK:

6.1 NEED FOR STUDY:

Compounds containing 1, 3, 4 oxadiazole nucleus find unique place in medicinal chemistry and play significant role as, they are associated with immense biological activity. 1,3,4 oxadiazole is reported to show some interesting pharmacological properties

1 1 7 6 3 like antipanosonal antibacterial , fungicidal , herbicidal, antitumor ,anti- inflammatory

9 10 1 10 2 anti T.B , diuretic , hypoglycemic , anticonvulsant and analgesic 1,3,4 oxadiazole derivatives have attracted considerable attention owing to their effective biological activity and extensive use. There are several methods available in literature for the synthesis of 1,3,4 oxadiazole. However, some of these methods suffer from disadvantages such as long reaction times, lower yield, requirement of severe conditions and using strong or toxic or costly reagent. Therefore, synthesis of new derivatives with greater efficacy and better yield still is desirables. It was observed from literature that certain five membered heterocyclic compounds posses interesting anti-inflammatory activity with lesser GIT side effects among them compound bearing 1,3,4 oxadiazole nucleus have been reported to have significant anti-inflammatory activity. In spite of availability and accessibility of many antibacterial and antifungal drugs in the market, most of them have fallen prey to the increased resistance of the bacterial and fungal microorganisms. In order to defeat this resistance, resistance mechanisms specificity and bacterial, fungal selectivity should be devised as the main targets for enhanced antibacterial and antifungal activity. Therefore, the present investigation comprises synthesis of some new oxadiazoles and to evaluate their biological activity.

6.2. REVIEW OF LITERATURE:

Desai et al1 have studies on 1, 3, 4 –oxadiazole derivative as potential antibacterial agent. They synthesized 5-(4-chlorobenzene) N aryl -1,3,4 oxadiazole 2-amine and screened for their antibacterial activity.

Shivanand et al2 synthesized new 2-(3-methyl-7 substituted–2 oxo quinoxalinyl)–5- (aryl) - 1,3,4 oxadiazole as NSAID and analgesia.

Amir et al3 synthesized 1,3,4 oxadiazole derivative as anti-inflammatory agent. They synthesized 1, 3, 4 oxadiazole derivative from 2, 4, 6 –trichlorophenol with 1) ethylchloroacetate anhydrous K2CO3 and dry acetone. 2) NH2NH2.H2O and absolute alcohol and done biological studies for anti-inflammatory.

Narwade et al4 searched on conventional and ultra sound mediated synthesis of oxadiazole. They synthesized Oxadiazole from acid hyadrazide on ultra sound irradiation with iodine/ potassium iodide and sodium hydroxide.

Mulwad et al5 synthesized and checked biological activity of thidiazolo 1, 3, 4, oxadiazole derivative.

Holla et al6 synthesized some 2-chloro-1, 4 bis (5-substituted 1, 3, 4 oxadiazole- zylmethyleneoxy) phenylene derivative having anticancer activity. 2-chloro 1,4 phenylenedioxide, bis-acetyl hydrazine on reacting with carboxylic acid in presence of phosphorus oxychloride affords 2-chloro bis, 1,3,4 oxadiazole 2,5disubstituted 1,3,4 oxadiazole posses activity like antibacterial, antifungal, antimalarial, anti convulsant, anti- inflammatory and anticancer.

Frank et al7 synthesized 1, 3, 4 oxadiazole carrying imidazole moiety for antibacterial and antifungal activity. Series of 1, 3, 4 oxadiazole derivatives have been obtained by cyclisation of various hydrazones with acetic anhydride. Shetgiri et al8 synthesized oxadiazole for antimicrobial. Series of oxadiazole synthesized from 2[oxyacetyl hydrazine] ethyl benzene.

Joshi et al9 synthesized acetyl oxadiazole bearing benzo thiophene nucleus as anti T.B. and antibacterial.

Sudha et al10 synthesized 5-(4-Aroyl)-aryloxy methyl-2-thio-1,3,4-oxadiazole by the intramolecular cyclisation of thiosemaicarbazides generated by action of hydrazide on carbondisulphide in presence of KOH in good yield.

Sangpure et al11 synthesized some 1, 3, 4 oxadiazole, thiadiazole, triazole and related compounds possessing benzofuran moiety and biological evaluated for antibacterial and antifungal activity.

Bhovi et al12 synthesized 2-methyl-3-ethoxycarbonyl-1-oxadiazolyl aminocarbonylmethylindoles. They screened the derivative for antimicrobial activity.

Mogolaiah et al13 synthesized 1,3,4-oxodiazolyl-1,8-napthypyridines and biological evaluated for antibacterial activity.

Mishra et al14 synthesized 1,2,4-triazolo and thiadiazolo [3,2-b]-1,3,4-oxadiazole with 6-thiones and checked their antifungal activity.

Lee et al15 has synthesized 1,3,4 oxadiazole having phenol and thiophenol group.

6.3. OBJECTIVES:

1. Synthesis of different substituted oxadiazole. 2. The purification of the compounds will be carried by recrystallization using suitable solvents, TLC, Column Chromatography, etc. 3. To characterize the structures of newly synthesized compounds by UV,IR, NMR, MASS Spectral technique. 4. To evaluate the biological activity of the newly synthesized compounds. ENCLOSURE: II

7. .METHODOLOGY

7.1 SOURCE OF DATA:

1. The literature survey will be done by referring chemical abstracts of all the national and international journals pertaining to synthetic, medicinal and pharmaceutical chemistry. 2. The information about pharmacological and biological activities will be collected by referring Indian Journals of Medicinal Chemistry, Current Medicinal Chemistry, Bio-organic Medicinal Chemistry, Indian Journal of Pharmaceutical Science, Indian drug and Bull. Korean Chem. Soc. etc 3. Library of Bharathi College of Pharmacy, Bharathinagara, Indian Institute of Science, Bangalore, IITC, Hyderabad, IIT, Chennai. 4. The day to day development in this area will be updated by literature survey through E-publishing & current periodicals in library of Bharathi College of Pharmacy, Bharathinagara. 5. All the basic facilities required for synthetic pharmaceutical chemistry are available in laboratories of Bharathi College of Pharmacy, Bharathinagara. For purification of the products TLC, Column Chromatography, HPLC & other facilities are also available in Bharathi College of Pharmacy Laboratories.

7.2 METHOD OF COLLECTION OF DATA:

The chemical structure of the synthesized compounds shall be established on the basis of physical, chemical and analytical data. Melting point of new compounds shall be determined in open capillary tube. They are expressed in degree Celsius.

The compound synthesized will be characterized by UV, IR, H1 NMR, C13 NMR & mass spectral data. This will be collected by sending the sample to other advanced research centers like IISC Bangalore, IICT Hyderabad & IIT Chennai. All the molecules will be screened for their biological activities in our laboratory.

7.3 Does the study require any investigation or interventions to be conducted on patients or other humans or animals?

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

Yes, attached institutional ethical clearance certificate

ENCLOSURE: III

8. REFERENCES:

1. Desai N.C., Bhavsar A.M., Shah M.D., and Saxena A., “Synthesis and QSAR studies of thiosemicarbazides,1,2,4 triazole, 1,3,4 thiadiazole, 1,3,4 oxadiazole derivatives as potential antibacterial agent”, Indian Journal of Chemistry, 2008; 47B: 579-589. 2. Wagle S., Adhikari A.V., and Kumari N.S., “Synthesis of new 2-(3-methyl-7- substituted-3-oxoquinoxalinyl)-5-(aryl) - 1, 3, 4 oxadiazoles as potential non steroidal anti inflammatory and analgesic agents”, Indian Journal of Chemistry, 2008; 47B: 439-448. 3. Amir M., Javed S.A., and Kumar H., “Synthesis of some 1,3,4 oxadiazole derivatives as potential anti-inflammatory agent”, Indian Journal of Chemistry, 2007; 46B:1014-1019. 4. Narwade S.K.,Halnor V.B.,Dalvi N.R.,Gill C.H., and Karale B.K., “ Conventional and ultrasound mediated synthesis of some thiadiazole, triazole and oxadiazole”, Indian Journal of Chemistry, 2006; 45B: 2776-2780. 5. Mulvad V.V., and Chaskar A.C., “ Synthesis and antibacterial activity of new oxodiazolo[1,3,5]-triazine, 1,2,4-triazolo and thidiazolo 1,3,4-oxodiazole derivatives”, Indian Journal of Chemistry, 2006; 45B:1710-1715. 6. Holla S.K., Narayana P.K., Bhat S., Mithun A., and Poojary B., “Synthesis and Anticancer activity studies on some 2-chloro-1,4 bis (5-substituted 1,3,4 oxadiazole-zylmethyleneoxy) phenylene derivative”, Indian Journal of Chemistry, 2005, 44B; 1669-1673. 7. Frank P.V. and Kalluraya B., “Synthesis of 1, 3, 4 oxadiazole carrying imidazole moiety”, Indian Journal of chemistry, 2005; 44B:1456-1459. 8. shetgiri N.P.and Nayak B.K., “ Synthesis and antimicrobial activity of oxadiazole, pthalazines and indolinones”, Indian Journal of Chemistry, 2005; 44B:1267-1272. 9. Vasoya S.L., Patel M.R., Dobaria S.V., Joshi H.S., “ Facile synthesis of some new azetidinone and acetyl oxadiazols bearing benzo[b]thiophene nucleus as potent biological active agent”, Indian Journal of Chemistry, 2005;.44B: 405-409. 10. Sudha B.S., Shashikant S., Khanum S.A. and Sriharsha S.N., “Synthesis and pharmacological screening of 5-(4-Aroyl)-aryloxy methyl-2-thio-1,3,4- oxadiazole”, Indian Journal of Pharmaceutical Science, 2003; 65(5):465-470. 11. Sangpure S.S. and Basawraj R., “Synthesis and biological activity of some 1,3,4 oxadiazole, thiadiazole, triazole and related compounds possessing benzofuran moiety”, Indian Journal of Pharmaceutical Science, 2004; 66(2): 221-226. 12. Bhovi M.G., Gadaginamath G.S., “Chemoselective reaction of indole 1,3- dicarboxylates towards hydrazine hydrate: Bishetrocycles: Synthesis and antimicrobial activity of some new 2-methyl-3-ethoxycarbonyl-1-oxadiazolyl /thiazolidinonyl/pyrrolyl-aminocarbonylmethylindoles”, Indian Journal of Chemistry ,2005; 44 B:1663-1668. 13. Mogilaiah K. and Vidya K., “Synthesis and antibacterial activity of 1,3,4 oxadiazolyl- 1,8 naphthyridine”, Indian Journal of Chemistry, 2006; 45B:1905- 1908. 14. Misra A.R., Sinh H., Yadav L.D.S. and Misra J. P., “Synthesis of 1,2,4-triazolo and thiadiazolo [3,2-b]-1,3,4-oxadiazole with 6-thiones as possible antifungal agents”, Indian Journal of Pharmaceutical Science, 1994; 56(1): 1-4. 15. Lee C.H., Cho H.I. and Lee K.J., “Synthesis of 1,3,4 oxadiazole having phenol or thiophenol group”, Bulletin of Korean Chemical Society, 2001; 22:1153-1155.