Synthesis and Antimicrobial Activity

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NOVEL THIADIAZOLE DERIVATIVES

M.PHARM

DISSERTATION PROTOCOL Submitted to

Rajiv Gandhi University of Health Sciences Bangalore, Karnataka

MOHAMMAD.YOUNUS B.Pharm.,

Under the Guidance of

Dr. KISHORE SINGH. C. M.Pharm, Ph.D. PROFESSOR & HOD

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY R.M.E.S’s COLLEGE OF PHARMACY, GULBARGA-585102 2011-2012 Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. Name of the candidate and MOHD.YOUNUS Address(In block letters): VILL& POST SHARIFNAGAR MORADABAD U.P -244602 2. Name of the Institution: R.M.E.S’s COLLEGE OF PHARMACY, GULBARGA 3. Course of study and subject: M.PHARM (PHARMACEUTICALCHEMISTRY) 4. Date of admission to course: 26/06/2010 5. Title of the topic: “SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NOVEL THIADIAZOLE DERIVATIVES”

6 Brief resume of this intended work 6.1 Need for the study Enclosure-I 6.2 Review of literature Enclosure-II 6.3 Objective of the study Enclosure-III 7 Material And Methods 7.1 Source of data Enclosure-IV 7.2 Method of collection of data Enclosure-V 7.3 Does the study require any investigation or interventions to be conducted on patients or other human beings or animals? If so NO please describe briefly. 7.4 Has ethical clearance been obtained from your institution in NO case of 7.3

8 List of References Enclosure-VI 9 Signature of the Candidate 10 Remarks of the Guide The above information and literature has been extensively investigated, verified and was found to be correct. The present study will be carried out under my supervision and guidance. Name and Designation of Dr.KISHORE SINGH .C. 11.1 Guide M.Pharm, Ph.D.

11.2 Signature

Mr.HANAMANTH J.KALLUR 11.3 Co-guide M.Pharm.

11 11.4 Signature

11.5 Head of the Department Dr. KISHORE SINGH. C. M.Pharm, Ph.D. PROFESSOR. & HOD DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

11.6 Signature

12 12.1 Remarks of the chairman The proposed work can be carriedout in our and the principal laboratory at R.M.E.S’s college of pharmacy, Gulbarga, Karnataka Dr. KISHORE SINGH. C. 12.2 Name of Principal M.Pharm, Ph.D. PROFESSOR.PRINCIPAL & HOD RMES`s COLLEGE OF PHARMACY GULBARGA-585102 Mobile No 09880200905

E-mail ID [email protected]

Signature

ENCLOSURE-I 6. BRIEF RESUME OF THE INTENDED WORK:

6.1. Need for the study:

Introduction

Thiadiazole have received considerable attention during last few decades as they are endowed with various biological activities having wide range of therapeutic properties. Various thiadiazole derivatives posses’ different pharmacological and biological activities of which the most potent is Cytotoxicity1, Anti-microbial and cytotoxic1,2,5,11,13,15, Anti-tumour3, CNS. Depressant4 . Anti- tuberculer17,14 . Anti-protozoal8 . Anti- convulsant9 . Anti-viral10 Herbicidal6 Research is never ending process; particularly drug discovery is a continuous process for a lot of reasons like:

 Some of the drugs are highly effective that are associated with toxic side effects.  The pathogenic organisms are known to develop resistance gradually against a particular drug; hence the drugs, which are active today, may become inactive after several years. In order to overcome this problem there is a need to replace old drugs by newer ones.  Some drugs have possessed allergic reaction to the some patients.  Nature always posses problem to the human races, through new pathogenic bacteria, fungi etc, that cause newer diseases.

Hence man is always in search of more potent and safer drugs than the existing ones. Thiadiazole is a part of heterocyclic chemistry which contains N and S, this compound possesses wide spectrum of biological activity and have wide range of therapeutic properties. Hence the present study is focusing on the development of new potent bioactive, less toxic and easily assembled molecule.

ENCLOSURE-II

6.2 Review of Literature:

Literature survey reveals that the Thiadiazole has received considerable attention during last two decades as they are endowed with variety of biological activities. These are few literature of Thiadiazole is as under:  Gundurao.kolavi et.al., have synthesized a series of Imidazo[2,1-b] [1,3,4]thiadiazole derivatives and they evaluate their anti-tubercular activity against Mycobacterium tuberculosis1.

 D.A Ibrahim has synthesized 3,6-di substituted [1,2,4] triazolo [ 3,4- b] [1,3.4] thiadiazole derivatives and they carried out their anti -tumor activity3

 D Manjunath Ghate et. al., have synthesized 3-alkyl 4-amino 5-mercapto 1,2,4-triazoles (3a-d) treated with different aromatic acid in the presence of phosphorus oxy chloride to yield 3-alkyl-6-aryl-1,2,4-triazolo[3,4b]- 1,3,4-thiadiazoles derivatives. All these new heterocycles were screened for their antibacterial, antifungal and anti-inflammatory activity 4

 R.shashikant pattan et. al., were carried out the synthesis of some 1,3,4- Thiadiazole derivatives and they evaluate their antibacterial and antifungal activity 6

 Ravi S. Lamani et. al., investigated the synthesis of novel methylene bridged benzioxazolyl imidazo[2,1-b] [1,3,4] thiadiazole derivatives from bezioxazolyl-3-acetic acid and thiosemicarbazide and they evaluate their antibacterial and antifungal activity.7

 Anelia Ts. Mavrova et. al., synthesized a series of 1,2,4-Triazole and 1,3,4-Thiadiazole derivatives and carried out there cytotoxic activity on immuno-competent cells 9

 Sabir Hussain et, al., synthesized a series of 1,2,4-triazole and 1,3,4 thiadiazole derivatives from 5-amino-2-hydroxy benzoic acid and carried out their antibacterial activity against S.aureus (gram positive) and E.coli (gram negative) bacteria and anti fungal activity against A.niger10

I II ENCLOSURE-III

6.3 Objectives of the study

The increasing clinical importance of drug resistance bacterial and fungal pathogens has lent additional urgency to anti-microbiological research and development of new anti-microbial compound. Hence we planned in the present objectives of the study will be as below:

 Development of synthetic method for the synthesis of some 1,3,4 Thiadiazole derivatives.

 Chemical characterization of newly synthesized compound by I.R., NMR and Mass spectral data.

 Biological screening of 1,3,4 Thiadiazole derivatives for antimicrobial activity. ENCLOSURE-IV

7. Material and Method:

7.1 Source of data:

The present project is synthesis and chemical characterization of some novel thiadiazole derivatives and their antimicrobial studies. All chemicals required for synthesis will be purchased from Aldrich and S D fine chemicals etc. The subject will be studied in detail by referring National and International journals of medicinal chemistry. Our college has E-library facility to browse all the journals and provide necessary assistance for the student to visit library at IICT, Hyderabad; IISC Bangalore and Gulbarga University Gulbarga, for the literature survey. All the basic facilities required for synthetic pharmaceutical chemistry is available in our college laboratories. For purification of the product TLC,Column chromatography, HPLC and other facilities such as vacuum pump , royary vacuum evaporators etc. are also available in our laboratory.

ENCLOSURE-V 7.2 Method of Collection of data:

The chemical structures of the synthesized compounds will be established on the basis of physical, chemical and analytical data. Purification of the synthesized compounds will be done by using re-crystallization techniques. Melting point of the newly synthesized compounds will be analyzed by using open capillary tube method.

The chemical characterization of the newly synthesized compounds will be confirmed by IR, NMR and Mass Spectral data is used for the characterization of the synthesized compounds by sending the samples to the other advaced research centres like IICT-Hyderabad, IIT-Chennai and IISc Bangalore, Quest Research centre and Astra Zeneca India Ltd. Bangalore . Antimicrobial activity will be carried out by Disc-diffusion method or cup-plate method in our laboratory.

Screening of Anti-bacterial activity by Disc-diffusion method:

Meat extract is taken and volume is made up 100ml with water and this were added weighed quantities of peptone,salt and agar.The contents were disolved by heating,the mixture was filtered and PH was adjusted to 7.5, the medium is sterilized by autoclaveing at 121C and then poured in 200ml quantities to petridishes. A loop full of an overnight broth culture is spread evenly over the whole part with sterile cotton-wool swab.

The culture plates were dried in the incubator with the lid until its surface was free from visible moisture. Without further delay,known concentration of the drugs was applied as drug discs (prepared by uniformly punching out 6mm discs from Whatmann filter paper No:1 and impregnation with drug 100 discs in 1ml) with adequate spacing to the surface of the culture plates with sterile fine pointed forceps and pressed gently to ensure full contact with the medium.it is then transferred quickly to the incubator and incubated for 24hrs at 37 C.After 24hrs the diameter zone of inhibition produced was measured in mm.

 Does the study require any investigation to be conducted on patients or other humans or animals? If so, please describe briefly.

NOT APPLICABLE

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

NOT APPLICABLE ENCLOSURE-VI References:

1. Anelia Ts. Mavorva, Diana Wesselinova, et.al. Synthesis, Cytotoxicity and effects of some 1,2,4-triazole and 1,3,4-thiadiazole derivatives on immuno-competent cells. European Journal of Medicinal Chemistry 44 2009: 63-69 2. V. Padmavathi, G.sudhakar Reddy, et.al. Synthesis, antimicrobial and cytotoxic activity of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4- triazoles. European Journal of Medicinal Chemistry 44 (2009):2106- 2112. 3. D.A.Ibrahim.et.al synthesis and biological evaluation of 3.6- disubstituted[1,2,4]triazolo[3.4-b][1,3,4]thiadiazole derivatives as a novel class of anti-tumuor agents. European journals of medicinal chemistry 44(2009):2776-2781 4. Varsha Jatav,Pradeep Mishra ,Sushil Kashaw ,J.P Stables. Synthesis and CNS depressant activity of some novel 3-[5-subtituted1,3,4-thiadiazole-2- yl] qunazoline-4(3H)-ones. European Journal of Medicinal Chemistry 43 (2008):135-141 . 5. Pattan Shashikant R., Desai N.S., Rabara P.A., Bukitgar A.A, Wakale V.S. Synthesis and antimicrobial evaluation of some 1,3,4- thiadiazole.Indian Journal of Pharmaceutical Education & Research Oct-Dec 42(4) (2008):314-318. 6. GUO Wan-cheng, LIU Xing-hai, LI Yong-hong, WANG Su-hua and LI Zheng-ming. Synthesis and Herbicidal activity of Novel Sulfonylureas containing Thiadiazole moiety. Chem. Res. Chinese. Universities. 24(1) ( 2008): 32-35 7. Gundurao Kolavi, Vinayak Hegde et.al. synthesis and evaluation of antitubarcular activity of imidazo[2,1-b] [1,3,4] thiadiazol derivatives.Bioorg.Med.Chem.14 (2006):3069-3080. 8. Samir A.carvalho, Synthesis and Anti-protozoal profile of new functionalized 1,3,4-thiadiazole-2-arylhydrazone derivatives , designed as non-mutagenic megazol analogues. Bioorganic and medicinal chemistry 14 (2004) 5967-5970 .

9. Hetice N.Dogan et.al . Synthesis of new 2,5-Disubstituted -1,3,4- thiadiazole and preliminary Evaluation of Anti-convulsant and antimicrobial Activities.Bioorganic and medicinal chemistry 10,2002; 2893- 2898. 10. Marina Kritsanida. et.al. Synthesis and Anti-viral activity evaluation of some new 6-substituted 3-(1-adamantyl) – 1,2,4 –triazolo[3,4-b][1,3,4] thiadiazoles . Il Farmaco 57 (2002) 253-257. 11. A.R. jalilian.et al. synthesis and in vitro anti-fungal and cytotoxicity evaluation of substituted 4,5 –dihydronaphtho[1,2-d]thiadiazole.il farmaco 58 (2003)63-68 12. Mohd. Amir.et al. Condensed bridgehead nitrogen heterocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4,-b]-1,3,4- thiadiazole derivatives of ibuprofen and bi phenyl-4-ylox acetic acid . Europian journal of Medicinal chemistry 48 (2008) 2056-2066. 13. Ravi S,Lamani et.al. synthesis and anti-microbial studies of some novel methylene bridged benzioxazolyl imidazo[2,1-b]thiadiazole derivatives. Europian journal of medicinal chemistry 44 (2009) 2828-2833. 14. S.Talath et al. Synthesis ,antibacterial and anti-tubercular activities of some 7-[4-(5-amino-[1,3,4] thiadiazole-2–sulfony]l-piperazine1-yl] fluroquinolonic derivatives. Europian journal of medicinal chemistry 41(2006) 918 -924 15. Kallanugouda R. et. al. Synthesis, characterization and antimicrobial activity evaluation of new 2,4-Thiazolidinediones bearing imidazo[2,1-b] [1,3,4]thiadiazole moiety. Arabian Journal of Chemistry 2010. 16. Ferniss B S, Hannaford A. J., Smith PWG, Patchel AR, Vogel’s Text book of Practical Organic Chemistry 5th Edition. 17. Jerry March, Reaction Mechanism and structure. Advance Organic Chemistry 4th Edition. 18. Ahluwalia V. K., Parshar R. K., Organic Reaction Mechanism 2nd Edition. Modern Methods of Organic Synthesis. William Carruthers and Iain Coldham. 4th Edition. .