“SYNTHESIS, CHARACTERIZATION AND
ANTI-MICROBIAL ACTIVITES OF 1, 2, 4-TRIAZOLE DERIVATIVES”
M.PHARM DISSERTATION PROTOCOL
SUBMITTED TO
Rajiv Gandhi University of Health Science Bangalore, Karnataka
BY
VINOD SUBHASH PATIL
B.Pharm
UNDER THE GUIDANCE OF
Dr. G.K.KAPSE
M.Pharm Ph.D
PROFESSOR
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
LUQMAN COLLEGE OF PHARMACY, GULBARGA-585102
2010-2011
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,
KARNATAKA
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the candidate Andaddress / VINOD SUBHASH PATIL
Luqman college of pharmacy,
old jewargi road,
gulbarga-585102.
2. / Name of the institution / Luqman college of pharmacy,
old jewargi road,
gulbarga-585102.
3. / Course of study and subject / master of pharmacy
(Pharmaceutical Chemistry)
4. / Date of Admission of course / 22-06-2010
5. / TITLE OF THE TOPIC / “SYNTHESIS,CHARACTERIZATION AND ANTIMICROBIAL ACTIVITIES OF 1,2,4-TRIAZOLE DERIVATIVES’’
6.
7. / Brief Resume of the intended work:
6.1 Need for the study:
Synthesis of new compounds to explore potential biological active agents still draw continuous interest; molecular manipulation, combination of biologically active moiety into one molecule and synthesis of totally newer moiety have been the methods of research. It is evident from survey of literature that only few compounds have come quite close to act as antimicrobial agent but none could prove totally lethal and none could suit all the criteria of an ideal chemotherapeutic agent in all cases. Hence, search for newer antimicrobial agent is a ceaseless pursuit to obtain drugs of high potential with least undesirable side effects. Such investigation that has been planned to carry-out in the present work is 1,2,4-triazole derivatives.
Some Schiff bases bearing aryl groups are heterocyclic residue possess excellent biological activity which has attracted many researcher’s attention in recent years1, 2, 3. Further it is evident from the literature survey that Schiff bases are used as substrate in the preparation of a number of industrial intermediates and biologically active compounds via ring closure, cycloaddition and replacement reactions4. More over, Schiff bases derived from various heterocycles have been reported to possess cytotoxic5, anti-convulsant6, antiproleferative7, antimicrobial8 and antifungal activity9. N-bridged heterocyclic derivatives derived from 1,2,4 triazoles shows varied biological activities such analgesic10, anti-HIV11 and anti-inflammatory property12.
Likewise, the triazole nucleus which incorporates N-C-S linkage exhibit large number of biological activities. 3,5-disubstituted 1,2,4 triazole and it’s derivatives have been reported to possess wide spectrum of activities .
These biological data promoted us to plan for synthesis of new Schiff bases bearing 1, 2, 4- triazole ring and evaluate for their anti-microbial properties.
6.2 Review of Literature:
The extensive literature survey revealed that compounds containing 1,2,4-triazole derivatives are reported to posses a wide range of biological activities and synthesis of these compounds which is clinically used as anti-microbial & anti- inflammatory substances. There are few important literature available for 1, 2, 4-triazole are as under:
Ø Kokil GR et al., (2010)13 have synthesised a novel triazole derivatives of 7-hydroxy-4 methylcoumarin using various substituted aromatic aldehydes and evaluated for their in vitro fungicidal activity against Candida albicans at various concentrations to obtain minimum inhibitory concentration(MIC).
Ø Singh RJ et al., (2010)14 have synthesized 4-aryl-5-(isomeric pyridoyl)-3H-1, 2, 4-triazoles as potent bacteriocidal agents against S. aureus, E.coli, B. subtilis and P.aeruginosa.
Ø Singh RJ et al., (2009)15 have synthesized a novel series of 3, 5-diaryl-4H-1, 2, 4-triazole derivatives as antifungal agent against P.oryzae, B. cinerea, A. niger, C. albicans and T. rubrm.
Ø Hussain S et al., (2008)16 have synthesized and evaluated them for antibacterial and antifungal activity using cup plate technique. The compounds showed significant antibacterial activity against S. aureus (gram-positive) and E.coli (gram-negative) and antifungal activity against A. niger.
Ø Rivera G et al., (2008)17 have developed an easy method for the synthesis of thirteen compounds derived from 1,2,4-triazoles through a carboxylic acid and hydrazinophthalazine reaction, with a 75-85% yield mediated by the use of agents such as 1-ethyl-3-(3´-dimethylaminopropyl)-carbodiimide hydrochloride and 1-hydroxybenzotriazole. The operational simplicity of this method and the good yield of products make it valuable for the synthesis of new compounds with pharmacological activity.
Ø Bekircan O et al., (2006)18 have synthesized a novel series of 4-arylidenamino-4H-1,2,4-triazole derivatives which show remarkable anticancer activity..
Ø Joshi HS et al., (2005)19 have synthesized a novel imidazolones and 1,2,4-triazoles and evaluated for in vitro antibacterial activity against Escherichia coli ATCC 25922, Proteus vulgaris ATCC 6380, Bacillus megaterium ATCC 14581, Staphylococcus aureus ATCC 29213, and antifungal activity against Aspergillus niger ATCC 9029. The in vitro antimycobacterial activity of the new compounds was also investigated against Mycobacterium tuberculosis H37RV (ATCC 27294) in BACTEC 12B medium using the ALAMAR radiometric system.
6.3 Objective of the study:
The present investigation includes.
Ø Synthesis of 3, 5-disubstituted 1, 2, 4 -triazole derivatives following literature method.
Ø Chemical Characterization of the newly synthesized compounds by IR, NMR, Mass spectral studies.
Ø Evaluation of the title compounds for their Anti-microbial ( Anti-bacterial, antifungal) activities.
Materials and Methods:
7.1 Method of collection of data:
The research work that will be carry-out in the laboratory by various experimental technique includes:
1. Synthesis of target molecules and determination of their physical constant, solubility, elemental analysis data will be done.
2. Spectroscopic data of new compounds i.e. I.R., NMR, Mass will be done for structural confirmation of the synthesized compounds.
3. Pharmacological screening for antimicrobial activity by Cup and Plate method and result will be compared with that of the standard.
7.2 Synthetic strategy:
The various potassium dithiocarbazinate are prepared from the reaction of hydrazones of different aryl acid with carbon disulphide and potassium hydroxide following known method. The potassium dithiocarbazinate thus prepared are reacted with hydrazine hydrate to produce cyclized product 1,2,4 -triazole derivatives. Then such triazole derivatives are suitably exploited so as to form Schiff bases using aryl aldehydes . The physical and analytical profile will be determined for the derivatives synthesized by conventional synthetic strategy.
8. / Scheme
Biological screening:
Anti-microbial activity16:-
All the compounds synthesized will be subjected to screening against both gram positive (Staphylococcus aureus, Bacillus subtilis) and gram negative (Escherichia coli, Klebsiella pneumonia) bacteria and antifungal activity against (Candiada albicans, Aspergillus flavus) by using Cup & Plate method in our laboratory and results will be compared with the known standard Anti- microbial agents.
7.3 Source of data:
1. From available literature.
2. From library based books.
3. Web sites
- www.sciencedirect.com.
- http://jgate-helinet.informindia.co.in
- www.pubmed.com.
- www.scirus.com.
- www.herbmed.com.
7.3-1 Assessment of toxic effect20:
As per OECD-425 guidelines.
7.4 Does the study require any investigations or interventions to be conducted on Patients or humans or animals? If so, please describe briefly.
NO
7.5 Has ethical clearance been obtained from your institution in case of 7.4?
NOT APPLICABLE
List of References:
1. Hetzhein A, Mockel K. Adv Heterocycle Chem.1996;7:183.
2. Sandstrom J. Adv Heterocycle Chem 1968;9,165.
3. Kohn EC, Liotta LA, US.Patent 637145(Chem. Abstr.1991;115,248099).
4. Kane JM, Wdudley M, Sorensen SM, Miller FP. J Med Chem.1988;31:1253.
5. Karia FD, Parsania PH. ‘’Synthesis, Biological and Thermal properties of Schiff bases of Bisphenol-C’’. Asian J Chem.1999;11:991-995.
6. Tarafder MT et al., ‘’S-Methyldithiocarbazate and its Schiff Base-Evaluation of bonding and biological Properties’’. J Biochem Mol Biol Biophs.2002;6:85-91.
7. Kucukguzel I, Kucukguzel SG, Rollas S, Otuk-Sans G, Ozdemir O, Bayrak I, Altug T; Stables, J. P. ‘’3-(arylalkylthio)-4-alkyl/-5-(4-aminophenyl)-4H-1,2,4-triazole derivatives and their anticonvulsant activity’’. Pharmaco.2004;4(59):893-901.
8. Vicini P, Geronikaki A, Incerti M, Busonera B, Poni G, Kabras CA, Colla PL. Synthesis and biological evaluation of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases. Bioorg. Med. Chem. 2003;11:4785-4789.
9. Bekircan O, Kahveci B, Kucuk M. Synthesis and anticancer evaluation of some new unsymmetrical 3,5-diaryl-4H-1,2,4-triazole derivatives. Tur J Chem 2006; 30: 29-40.
10. Xin YL, Wen FX, Jing D W 2003; 790-793.
11. Olcay B and Hakan B. Tur J Chem 2008; 2126-2135.
12. Neslihan D, Ahmet D, Sule C, Deniz S, Turk J Chem 2008;32:1-8.
13. Ganesh R. Kokil, Prarthana V. Rewatkarb, Sandeep Gosainc, Saurabh Aggarwalc, Arunima Vermac, Atin Kalrac and Suresh Thareja; Synthesis and In Vitro Evaluation of Novel 1, 2, 4-Triazole Derivatives as Antifungal Agents; Letters in Drug Design & Discovery, 2010, 7, 46-49
14. Singh RJ, Singh DK. ‘’Novel Syntheses of Some 1, 2, 4-Triazoles as Potent Bacteriocidal Agents’’. E-Journal Chem.2010;7(1):37-40.
15. Singh RJ, Singh DK. ‘’Syntheses of Some 3,5-Diaryl-4H-1,2,4-triazole Derivatives and their Antifungal Activity’’. E-Journal Chem.2009;6(S1):S219-S224.
16. Hussain S, Sharma J, Amir M. ‘’Synthesis and Antimicrobial Activities of 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives of 5-Amino-2-Hydroxybenzoic Acid’’. E-Journal Chem.2008;5(4):963-968.
17. Gildardo R, Virgilio BG. ‘’An easy and direct method for the synthesis of 1,2,4-triazole derivatives through carboxylic acids and hydrazinophthalazine’’. Quim. Nova.2008;31(3):536-538.
18. Bekircan O, Kahveci B, Kucuk M. ‘’Synthesis and Anticancer Evaluation of Some New Unsymmetrical 3,5-Diaryl-4H-1,2,4-Triazole Derivatives’’. Turk J Chem.2006;30:29-40.
19. Thaker K, Zalavadiya P, Joshi HS. ‘’Synthesis of some New Imidazolones and 1,2,4-Triazoles Bearing Benzo[b]thiophene Nucleus asAntimicrobial Agents’’. Journal of Sciences, Islamic Republic of Iran.2005;16(2):139-144.
20. New OECD 425 guideline for testing animals; 2001: 1/26, 1-6.
9. / SIGNATURE OF CANDIDATE / VINOD SUBHASH PATIL
10. / REMARKS OF THE GUIDE / The candidate is working under my direct supervision in laboratories of L.C.P Gulbarga-585102
11. / 11.1 NAME AND DESIGNATION OF
GUIDE /
Dr. G.K.KAPSE
M.Pharm. Ph.D
PROFESSOR
11.2 SIGNATURE
11.3 CO- GUIDE /
11.4 SIGNATURE
11.5 HEAD OF DEPARTMENT / Prof. SUDHEENDRA
M.Pharm. (Ph.D.)
11.6 SIGNATURE
12. / REMARKS OF THE CHAIRMAN AND PRINCIPAL / The result of proposed investigation would be of significance for researchers. Hence, the proposed plan of work is recommended for registration.
12.1 SIGNATURE OF THE PRINCIPAL / PROF. SYED Sanaullah
M. Pharm. (Ph.D.)
Principal