“SYNTHESIS, CHARACTERIZATION AND DOCKING STUDIES OF SOME NEW THIAZOLE/ THIOPHENE DERIVATIVES AND THEIR IN-VITRO ANTI-MICROBIAL SCREENING ”

SYNOPSIS FORM.PHARM. DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCESKARNATAKA

BYMs. SUSMITA DATTA

I M.PHARMDEPARTMENT OF PHARMACEUTICAL CHEMISTRY

PES COLLEGE OF PHARMACYBANGALORE-560 050

(2012-2014)

1

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. Name of the candidate and address

Ms. SUSMITA DATTA Ι. M. PHARM(PHARMACEUTICAL CHEMISTRY)PES COLLEGE OF PHARMACYHANUMANTHANAGARBANGALORE-560 050

PERMANENT ADDRESS:C/O Mrs. RENU BANIKF.D-402 SECTOR-IIISALT LAKE CITYKOLKATA- 700106

2. Name of the institution PES COLLEGE OF PHARMACYHANUMANTHANAGARB.S.K.1st STAGEBANGALORE:-560 050

3. Course of the study MASTER OF PHARMACY (PHARMACEUTICAL CHEMISTRY)

4. Date of Admission 15th MAY 2012

5. Title of the topic:“SYNTHESIS, CHARACTERIZATION AND DOCKING STUDIES OF SOME NEW THIAZOLE /THIOPHENE DERIVATIVES AND THEIR IN-VITRO ANTI-MICROBIAL SCREENING ”

(1) (2) The active amino group will be further derivatized with different aromatic aldehydes, acid chlorides and acid anhydrides, to get the proposed title compounds.

2

6. BRIEF RESUME OF THE INTENDED WORK

6.1 Need for the study: The discipline of medicinal chemistry is devoted to the discovery and development of new agents for treating diseases. Most of this activity is directed to new natural or synthetic compounds.The major thrust area of research, on going in the field of medicinal chemistry includes synthesis and biological activity of heterocyclic compounds. Heterocyclic compounds hold a special place among pharmaceutically important natural and synthetic materials.

Among the heterocyclic compounds, sulphur and nitrogen containing moieties have attracted maximum attention, as they are full of useful ramifications especially in the biological and industrial fields. Thaizoles and Thiophenes nucleus in particular is the center of attraction in developing various essential moieties in pharmaceutical industries.

THIAZOLES:

Currently the azoles are one of the most important class of nitrogen containing heterocyclic compounds under investigation. Azoles are sub divided into thiazole, thiadiazoles, diazole imidazoles ,diazoles and pyrazoles according to their number and position of the nitrogen atoms in the five memebered rings.

Thiazoles are compounds having a five membered ring system along with the presence of sulphur and nitrogen as hetero atoms placed at positions 1 and 3 respectively and they are proven to be possessing good anti-microbial activity.

THIOPHENE:

Various substituted and condensed thiophenes have been reported to possess an array of pharmacological & biological properties including antimicrobial1 antioxidant, anticancer, analgesic, anticonvulsant activities.

As a result of remarkable pharmacological efficiency of Thiazole / Thiophene derivatives, intensive research has been synthesis ad focused on antimicrobial activity of the above mentioned nuclei.

A thiophene is a heterocycle having the molecular formula C4H4S consisting of a five- membered ring, which is aromatic as indicated by its extensive substitution reactions. Among the anti-microbial agents thiophene derivatives are known to have a promising activity.

3

6.2 Review of the literature :

References pertaining to Thiazoles:

1. N.C.Desai, et.al reported the synthesis of some thiazole derivative.[2013]

(3)

2. Chandresh .L, et.al reported the synthesis and anti microbial activity of3-substituted thiophenes.[2012]

(4)

3. N.Padmavathi, et.al reported the synthesis and anti-microbial activity of amido linked thiozaloes. [2011]

(5)

4

4. Nuray Ulusoy Guzeldemirci,et.al reported the synthesis and antimicrobial activity of 1,2,4- thiazoles .[2010]

(6)

5. Stanton Hon Lung Kok, et.al synthesized some novel 2, 4-disubstituted diazoles of the type as possible anticancer activity.[2008].

(7)

6. Koti RS, et. al has synthesized N-(5-formyl-4-methylthiazol-2-yl)acetamide which is having potent antimicrobial activity against two strains of bacteria and fungi.[2006].

(8)

5

7. Cukurovali A, et. al have synthesized and reported the anti bacterial on Gram positive bacteria, Staphylococcus aureus , Bacillus subtilis and two Gram negative bacteria , Salmonella typhimurium, Escherichia coli and anti fungal activity of some new substituted diazoles.[2006].

(9)

8. Vicini, et. al have synthesized and reported the anti microbial activity of (2E,5E)-5-benzylidene-2-(thiazol-2-ylimino)thiazolidin-4-one [2006].

(10)

9. Narayana B , et. al had reported the synthesis of 5-(2- amino thiazol-4-yl)-2-hydroxy benzamide as anti- fungal agents.[2004].

(11)

6

10. Woods, et. al reported the synthesis and cox-2 inhibitory action of some new substituted diazoles.[2001]

(12)

References pertaining to Thiophenes:

11. Aly H.M,et.al reported the design and synthesis of some new thiophene, thienopyrimidine

derivatives of antipyrine as potential antimicrobial agents.[2011]

(13)

7

12. Gouda Ma, et. al reported the synthesis and antimicrobial activities of some new thiazole and

pyrazole derivatives based on 4,5,6,7-tetrahydrobenzothiophene moiety.[2010]

(14)

13. Khalil A.M ,et.al reported the synthesis and antibacterial activity of some new thiophene

derivatives.[2009]

R=COCH3,COOC2H5, CN (15) 14. Raghuprasad, et. al reported the synthesis and antimicrobial activity of some thiadiazolo

thienopyrimidines .[2007]

R=OCH3 (16)

8

15. Queiroz M-JRP, et.al reported the synthesis and antimicrobial activity studies of hetero

aromatic tetra cyclic systems in the benzo[b] thiophene series.[2006]

X=N,S,O

(17)

16. Tehranchian S, et.al reported the synthesis and antibacterial activity of 1-[1,2,4-triazol-3-yl]

and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydro-benzo[c] thiophen-4[5H]ones.[2005]

(18) Where R = Me, Et, Cyclohexyl, etc.

17. Ferreira ICFR, et .al reported the antimicrobial activity of diaryl amine in the 2,3,5-trimethyl

benzo[b]thiophene series: a structure-activity evaluation study.[2004]

Where R3 = F, R4 = H (19) R3 = H, R4 = F

18. Saravanan ,et. al reported the synthesis, characterization and anti- bacterial activity of some

9

Schiff bases of 2-amino-3- (N-tolyl carboxamido)-4,5-pentamethylene thiophenes.[2003]

(20)

19. Saravanan, et. al reported the synthesis and antimicrobial activity of some 2-substituted amino

(2-methyl oxadiazol-5-yl)-4,5,6,7-tetrahydro benzo(b) thiophenes.[1998]

(21)

20 .Saravanan ,et .al reported the synthesis of some tetrahydro benzo[b]thiophenes as potential

antimicrobial agents.[1997]

(22)

In the view of the above observations it was thought of interest to synthesize and screen some new clubbed Thiazoles / Thiophenes for anti-microbial activity

SCHEME FOR THIAZOLES:

10

SCHEME FOR THIOPHENE:

11

6.3 OBJECTIVES OF THE STUDY:

12

1. To achieve the synthesis of some new Substituted Thiazoles /Thiophenes adapting standard protocols.

2. The purity and progress of the reactions will be monitored by TLC.

3. The purification of the compounds will be carried out by recrystallization using suitable solvents.

4. To characterize the structures of newly synthesized compounds by UV, IR, NMR, and MASS spectra.

5. To carry out the docking studies for the new compounds

6. To evaluate the anti-microbial activity of newly synthesised compounds by standard protocols .

7. To publish the research work in peer reviewed journals.

13

7. 7.1 MATERIALS AND METHODS:

Chemicals and other reagents will be purchased from standard companies. The progress of the reactions will be monitored by micro thin layer chromatography. The standard protocols will be followed for purification of the products. Structures of the synthesized molecules will be confirmed by the analytical and spectral data. Docking studies are done by using Hex as software.

7.2 Sources of data

IISC LIBRARY, BANGALOREPESCP LIBRARY, BANGALORERGUHS DIGITAL LIBRARY (Helinet)CENTRAL COLLEGE LIBRARY, BANGALORE

7.3 Method of collection of data

Chemical Abstracts, Journals like Indian Journal of Chemistry, Journal of Medicinal Chemistry, Indian Journal of Heterocyclic Chemistry, Journal of American Chemical Society, Indian Journal of Pharmaceutical Sciences, Journal of Organic chemistry, European Journal of Medicinal Chemistry, Tetrahedron, Bioorganic & Medicinal Chemistry and Helinet .

7.4 Pharmacological evaluation:

Evaluation of anti-microbial activity will be carried out by using cup-plate method.

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

-NOT APPLICABLE-

7.6 Has ethical clearance been obtained from your institution in case of 7.4? NOT APPLICABLE

14

8. LIST OF REFERENCES:

1. Harinath Y, Harikishore KRD, Naresh KB, Apparao C, Seshaiah K. Synthesis, spectral

characterization and antioxidant activity studies of a bidentate Schiff base, 5-methyl thiophene-2-

carboxaldehyde-carbohydrazone and its Cd(II), Cu(II), Ni(II) and Zn(II) complexes.

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. [Research]. 2013

15;101:264-72.

2. Mansour SA-S, Mahmoud SB, Saleh IA-q, Mostafa MG. Anti-breast cancer activity of

some novel 1,2-dihydropyridine, thiophene and thiazole derivatives. European Journal of

Medicinal Chemistry. 2011;46:137-41.

3. Issa MF, Mohamed AR, Seham E-Bb, Omar MAE-S, Siham ME-S. Synthesis and

pharmacological evaluation of 2-substituted benzo[b]thiophenes as anti-inflammatory and

analgesic agents. European Journal of Medicinal Chemistry. 2009;44:1718-25.

4. Ravi K, Airody VA, James PS. A new class of anticonvulsants possessing 6 Hz activity:

3,4-Dialkyloxy thiophene bishydrazones. European Journal of Medicinal Chemistry.

2009;44:4376-84.

5. Desai N, Atul HM, Rajpara K. Synthesis and study of 1,3,5-triazine based thiazole

derivatives as antimicrobial agents. Journal of Saudi Chemical Society. 2013.

6. Chandresh LJ, Natvar AS, Satish FV, Tarosh SP, Ritu BD, Bharat CD. Microwave

promoted synthesis and antimicrobial activity of 3-thiazole substituted 2-styryl-4(3H)-

quinazolinone derivatives. Journal of Saudi Chemical Society. 2012;16:363-9.

7. Padmavathi V, Prema kC, Venkatesh B, Padmaja A. Synthesis and antimicrobial activity

of amido linked pyrrolyl and pyrazolyl-oxazoles, thiazoles and imidazoles. European Journal of

Medicinal Chemistry. 2011;46:5317-26.

8. Nuray UGz, Omer Kçk. Synthesis and antimicrobial activity evaluation of new 1,2,4-

triazoles and 1,3,4-thiadiazoles bearing imidazo[2,1-b]thiazole moiety. European Journal of

Medicinal Chemistry 2010;45:63-8.

9. Staton HlK, Roberto G, Chung HC, Marcus CWY, Eva L, Raymond SMW, et al.

Synthesis and anti-cancer activity of benzothiazoles contining pthalimide on human carcinoma

cell lines. Bioorgaic & Medicinal Chemistry. 2008;16:3626-36331.

15

10. Koti R, Kolavi G, Hegde V, Khazi I. Vilsmeir Haack reaction of substituted 2-acet

amidothiazole derivatives and their anti-microbial activity. Indian J Chem. 2006;45(B):1900-4.

11. Cukurovali A, Yilmaz I, Gur S, Kazaz C. Synthesis and anti-bacterial and anti-fungal

activity of some new thiazolylhydrazone derivatives containing 3-substituted cyclobutane ring.

Eur J Med Chem. 2006;41(2):201-7.

12. Vicini P, Geronikaki A, Incerti M, Zani F. Synthesis and anti-microbial activity of some

novel 2-thiazolylimino-5-arylidene-4-thiazolidinones. Bioorg Med Chem. 2006;14(11):3859-64.

13. Narayana B, Raj K, Ashalatha B, Kumari N, Sarojini B. Synthesis of some new 5-(2-

substituted-1,3-thiazol-5-yl)-2-hydroxy benzamides and their 2-alkoxy derivatives as possible

anti-fungal agents. Eur J Med Chem. 2004;39(10):867-72.

14. Woods K, McCroskey R, Michaelides M, Wada C, Hulkower K, Bell R. Thiazol

analogues of the NSAID indomethacin as selective COX-2 inhibitors. Bioorg Med Chem.

2001;11(10):1325-8.

15. Aly H, Saleh N, Elhady H. The design and synthesis of some new thiophene,

thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents.

Eur J Med Chem. 2011;46:4566-72.

16. Gouda M, Berghot M, Abd E-GG, Khalil A. The synthesis and antimicrobial activities of

some new thiazole and pyrazole derivatives based on 4,5,6,7-tetrahydrobenzothiophene moiety.

Eur J Med Chem. 2010;45:1338-45.

17. Khalil A, Berghot M, Gouda M. Synthesis and antibacterial activity of some new thiazole

and thiophene derivatives. Eur J Med Chem. 2009;44.

18. Raghuprasad M, Mohan S, Das B, Srivastava S. Synthesis and antimicribial activity of

some thiadiazolo thienopyrimidines. Asian J Chem. 2007;19(5):2813-7.

19. Queiroz M-J, Ferreira I, Gaetano Y, Kirsch G. Synthesis and anti-microbial activity

studies of ortho-chlorodiarylamines and heteroaromatic tetracyclic systems in the

benzo[b]thiophene series. Bioorg Med Chem Lettr. 2006;10:4825-8.

20. Tehranchian S, Akbarzadeh T, Fazeli M, Jamalifar H. Synthesis and anti-bacterial activity

of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydro-

benzo[c]thiophen-4[5H]ones. Bioorg Med Chem Lettr. 2005;15:1023-5.

16

21. Ferreira I, Calhelha R, Estevinho L, Queiroz M-J. Screening of anti-microbial activity of

diaryl amine in the 2,3,5-tri methyl benzo[b] thiophene series: a structure-activity evaluation

study Bioorg Med Chem Lettr. 2004;14:5831-3.

22. Saravanan J, Mohan S. Synthesis of some 2-amino-3-(N-tolyl carboxamido)-4,5-

pentamethylene thiophenes as potential anti-bacterial agents. Asian J Chem. 2003;15(2):625-8.

23. Saravanan J, Mohan S. Synthesis and anti-microbial activity of some 2-substituted

amino(2-methyl oxadiazol-5-yl)-4,5,6,7-tetrahydro benzo(b)thiophenes. Indian J Hetero Chem.

1998;7:285-8.

24. Saravanan J, Mohan S, Nargund L, Shishoo C. Synthesis of some benzo (b)thiophenes as

potential anti-microbial agents. Indian J Hetero Chem. 1997;6:203-6.

9 Signature of the candidate : Ms. SUSMITA DATTA

10. Remarks of the guide: FORWARDED WITH REQUEST FOR APPROVAL

11. Name and designation of: 11.1 GUIDE

11.2 SIGNATURE

Mrs. Kavitha P.NAssistant Professor

Department of Pharmaceutical Chemistry,PES College of Pharmacy

Bangalore- 560 050

11.3 CO-GUIDE

11.4 SIGNATURE

NOT APPLICABLE

17

11.5 HEAD OF THE DEPARTMENT

11.6 SIGNATURE

Dr. J. SaravananProf. and HOD

Department of Pharmaceutical Chemistry,PES College of Pharmacy

Bangalore- 560 050

12. 12.1 REMARKS OF THE PRINCIPAL:

12.2 SIGNATURE: Prof. Dr. S. Mohan Principal & Director, PES College of Pharmacy, Bangalore-560 050

18