SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NEW SERIES OF MERCAPTO SUBSTITUTED 1,3,4- OXADIAZOLE DERIVATIVES.

M. Pharm. Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560041

By

MR. MD.AMEEN SIDDIQUI B.PHARM

Under the Guidance of

SRI. S. S. PUROHIT M. PHARM, (Ph.D.)

LECTURER,

DEPT. OF PHARMACEUTICAL CHEMISTRY,

S.E.T.’s College of Pharmacy,

S. R. Nagar, Dharwad, Karnataka -580002

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES-KARNATAKA, BANGALORE.

ANNEXURE –II

PROFORMA FOR REGISTRATION OF SUBJECT DISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS / MR. MD.AMEEN SIDDIQUI
DEPT. OF PHARMA CHEMISTRY
SET’S COLLEGE OF PHARMACY
S.R.NAGAR,
DHARWAD- 580002.
2. / NAME OF THE INSTITUTION / SET’s COLLEGE OF PHARMACY
S. R. NAGAR,
DHARWAD-580002.
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN
PHARMACEUTICAL CHEMISTRY
4. / DATE OF ADMISSION TO THE COURSE / JUNE-2012
5. / TITLE OF THE TOPIC:
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF A NEW SERIES OF MERCAPTO SUBSTITUTED 1,3,4- OXADIAZOLE DERIVATIVES.
6.0
7.0
8.0 / BRIEF RESUME OF THE INTENDED WORK:
6.1Need for the study:
Heterocyclic chemistry is the chemistry branch dealing exclusively with synthesis, properties and applications of heterocyclics especially vital to drug design.
Incorporation of an oxygen, a nitrogen, a sulfur, or an atom of a related element into an organic ring structure in place of a carbon atom gives rise to a heterocyclic compound. Since the heterocyclic atom must form more than one bond in order to be incorporated into a ring structure, halogens do not form heterocyclic compounds although they may be substituents on a heterocyclic ring structure. Heterocyclic compounds, like polycyclic ring compounds, are usually known by non-systematic names. Azoles are five membered heterocyclic compounds containing in their rings one or more heteroatoms, at least one of which is nitrogen.Standard drugs used in some of the medicinally important derivatives containing pyrazoles (azoles) are Novalgin,Aminopyrine etc. which possess NSAID properties. Apart from this, imidazoles, triazoles possess different biological activities like antimalarial, hypertensive and antifungal.2
The presence of Oxygen and Nitrogen in heterocyclic system has attracted the attention of medicinal chemists because of the diverse biological activities and profound efficacy.3Five memberedheterocycles with two carbon atoms, two nitrogen atoms and one oxygen atom are called Oxadiazoles. Depending upon the orientation of the nitrogen atoms they are described as 1,2,3-, 1,2,4-, 1,2,5-, 1,3,4- Oxadiazoles.

Oxadiazoles possess antitubercular,18muscle relaxant,4antiviral,5 analgesic,6anti-cancer,19anticonvulsant,20 anti-inflammatory,21hypotensive,7 antimicrobial,22 anthelmintic,8properties.
So, there is an urge to synthesize more potent derivatives containing these atoms and this research is an attempt to synthesize better,effective Oxygen & Nitrogen heterocyclic derivatives.
6.2Review of literature:
Extensive literature survey was carried out in libraries of SET’s College of Pharmacy Dharwad and KLE’s College of Pharmacy Belgaum. Karnataka University, Dharwad and by visiting various web sites through internet the relevant data has been collected.
Literature review showed following important Oxadiazole derivatives of pharmacological importance.
  1. Palak K. Parikhet.al., have reported synthesis and biological evaluation of 1,3,4-oxadiazolederivatives as potential antibacterial and antifungal agents.
.

  1. Mojahidulislamet.al., have reported synthesis and antimicrobial activityof some novel oxadiazole derivatives.

R=Phenyl, m-Xyly, P-tolyl, P-Chlorophenyl
  1. ZaferAsimKaplancikliet.al., have reported Synthesis of Some Oxadiazole Derivatives as New Anticandidal Agents.

R=P-Cl, m-Cl, H
  1. ShasikantR.Pattanet.al., have reported Synthesis and evaluation of some novel substituted 1,3,4,Oxadiazole and pyrazole derivatives for anti-tuberculer activity.


  1. WeimingXuet.al.have reported Synthesis and Antifungal Activity of Novel Sulfone Derivatives Containing 1,3,4-Oxadiazole Moieties.


  1. Qing-Cai Jiaoet.al.,have reported Synthesis, biological evaluation, and molecular docking studiesof 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents.

R=2me-C6H4, 4-F-C6H4, 4NH2-C6H4
  1. Mohammad Shaharyaret.al.,have reported Oxadiazolemannich bases: Synthesis andantimycobacterial activity.

R1=C6H5 , R2=Furfuryl
R1=C6H5, R2=phenyl
  1. Anil N. Mayekaret al., have reported Synthesis and Antimicrobial Studies on New Substituted 1,3,4-OxadiazoleDerivatives Bearing 6-Bromonaphthalene Moiety.


6.3Objectives of Study:
1)To synthesize a new series of mercapto substituted1,3,4-oxadiazole derivatives of highest purity.
2)To characterize the structure of the newly synthesized compound by different analytical techniques such as IR, NMR and Mass spectral data.
3)To evaluate the synthesized compounds for different biological activities.
Materials and methods:
7.1Source and Collection of data:
Chemical Abstracts.
Indian Journal of Chemistry.
Indian Journal of Heterocyclic Chemistry.
Journal of Medicinal Chemistry.
Journal of Heterocyclic Chemistry.
European Journal of Medicinal Chemistry.
Bioorganic and Medicinal Chemistry Letters.
Word wide web.
J-Gate@ Helinet etc.
7.2 Method of collection of Data:
A) Synthesis of the compounds:
Chemicals and other reagents required for synthesis will be procured from standard company sources. Compounds will be synthesized by using standard techniques. The reactions will be monitored by TLC. Purification of the compound will be done by standard procedures like recrystallization.
B) Characterization of the compounds:
The synthesized compounds will be characterized by preliminary laboratory techniques such as melting point, boiling point etc. Compounds synthesized will be confirmed by FTIR, Mass Spectroscopy and NMR spectral data. The Mass and NMR spectral data of the synthesized compound will be collected by sending the compounds to research centers like IISc, Bangalore.
C) Antimicrobial evaluation:
C-1) In vitro evaluation of antibacterial activity.25
The MIC determination of the synthesized compounds will be carried out in side-by-side comparison with Ciprofloxacin and Norfloxacin against Gram-positive (Staphylococcus aureus, Bacillussubtilis) and Gram-negative bacteria (Klebsiellapneumoniae, Escherichia coli) by broth microdilution method.Serial dilutions of the test compounds and reference drugs will be prepared in Mueller Hinton agar. Drugs (10 mg) will be dissolved in dimethylsulfoxide (DMSO, 1 ml). Further progressive dilutions with melted Mueller Hinton agar will be performed to obtain the required concentrations of 1, 2, 4, 8, 16, 31.25, 62.5, 125, 250 and 500 mg/ml. The tubes will be inoculated with 105cfu/ml (colony forming unit/ml) and incubated at 37oCfor 18 h. The MIC will be the lowest concentration of the tested compound that yields no visible growth on the plate. To ensure that the solvent will have no effect on the bacterial growth, a control will be performed with the test medium supplemented with DMSO at the same dilutions as used in the experiments.
C-2) In vitro evaluation of antifungal activity.26,27
The MIC determination of the synthesized compounds will be carried out in side-by-side comparison with Fluconazole and Griseofulvin against Candida Albicans,Candida neoformans, Aspergillusnigerand Aspergillusflavus by broth microdilution method. Serial dilutions of the test compounds and reference drugs will be prepared in sabouraud dextrose agar broth. Drugs (10 mg) will be dissolved in dimethylsulfoxide (DMSO, 1 ml). Further progressive dilutions with melted sabouraud dextrose agar brothwill be performed to obtain the required concentrations of 1, 2, 4, 8, 16, 31.25, 62.5, 125, 250 and 500 mg/ml. MIC values were read after 1 day for Candida species and Candida neoformans, and 2 days for Aspergillusniger, Aspergillusflavus in 37oC. The inoculum sizes contained approximately 1105cells/ml. The MIC will be the lowest concentration of the tested compound that yields no visible growth on the plate. To ensure that the solvent will have no effect on the fungal growth, a control will be performed with the test medium supplemented with DMSO at the same dilutions as used in the experiments.
7.3 Does the study require any investigation or interventions to be conducted on
patients or other humans/animals? If so please describe briefly.
No.
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Not applicable
REFERENCES:
  1. Alagwadi KR, Suresh S, Pattan SR, Pujar GV, Javali MC. Synthesis and antimicrobial evaluation of some 2-substituted oxadiazoles. Indian J heterocyclChem 2007;17:93-94.
  2. Almasirad A, Vousooghi N, Tabatabai SA, Kebriaeezadeh A, Shafiee A. Synthesis anticonvulsant and muscle relaxant activities of substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole. ActaChimslov 2007;54:317-24.
  3. Kim RM, Rouse EA, Chapman KT, Schleif WA, Olsen DB, Stahlhut M. et al. P1’ oxadiazole protease inhibitors with excellent activity against native and protease inhibitors–resistant HIV-1. Bioorg Med ChemLett 2004;14:4651-54.
  4. Vagadevi 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 HeterocyclChem 2001;10:253-60.
  5. Tyrkov AG, Tyurenkov IN, Timchenko MV, Perfilova VN. Hypertensive activity of 3-aryl-5-nitromethyl-1,2,4-oxadiazoles and their alkyl substituted derivatives. PharmChem J 2006;40:240-42.
  6. Manjunath SY, Biradar JS, Raga B. Synthesis and anthelmintic activity of triheterocycles: [5’-(5”-substituted-3”-phenylindol-2”-yl)-1’,3’,4’,-oxadiazol-2’-yl-thiomethyl] benzimidazoles. Indian J HeterocyclChem 2009;18:321-24.
  7. Parikh KP, Marvaniya HM, Sen DJ, synthesis and biological evaluation of 1,3,4-oxadiazole derivatives as potential antibacterial and antifungal agents. International J of Drug Development & Research2011;3(2):248-255.
  8. Islam M, siddiqui AA, Ramadoss R, Bhakt A, Goyal S, synthesis and antimicrobial activity of some novel oxadiazole derivatives. ActaPoloniaePharmaceutica n Drug Research 2008;65(4):441-447.
  9. Kaplancikli ZA, Synthesis of Some Oxadiazole Derivatives as New Anticandidal Agents. Molecules2011;16: 7662-7671.
  10. Pattan SR, Rabara PA, Pattan JS, Bukitagar AA, Wakale VS, Musmade DS, Synthesis and evaluation of some novel substituted 1,3,4,Oxadiazole and pyrazole derivatives for anti-tuberculer activity. Indian J of Chem 2009;48B:1453-1456.
  11. Xu M, He J, He M, Han F, Chen X, Pan Z, Wang J, Synthesis and Antifungal Activity of Novel Sulfone Derivatives Containing 1,3,4-Oxadiazole Moieties.Molecules2011;16: 9129-9141.
  12. Xiao QC, Zhu HL, Cheng K, Zheng QZ, Zhang XM, Synthesis, biological evaluation, and molecular docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents. Bioorganic & Medicinal Chemistry 2010;18:7836–7841.
  13. Yar MS, Siddique AA, Ali A,Synthesis and Anti Tuberculostatic Activity of Novel 1,3,4-Oxadiazole Derivatives.Journal of the Chinese Chemical Society, 2007;54:5-8.
  14. Mayeker AN, Yathirajan HS, Narayana B, Sarojini BK, Suchetha N, Synthesis and Antimicrobial Studies on New Substituted 1,3,4-Oxadiazole Derivatives Bearing 6-Bromonaphthalene Moiety.Int. J of Chem 2010;2(1):38-54.
  15. Chaudhari BR, Shinde DB,Shingare MS. Synthesis of some 1,4-benzothiazinyl thiosemicarbazides, triazoles,oxadiazoles,thiadiazoles and their antitubercular activity. Indian J HeterocyclChem 1995;4:187-90.
  16. Holla BS, Poorjary KN, Bhat KS, Mithun A, Poojary B. Synthesis and anticancer activity studies on some 2-chloro-1,4-bis-(5-substituted-1,3,4-oxadiazol-2-ylmethyleneoxy)phenylene derivatives. Indian J chem 2005;44B:1669-73.
  17. Lankau HJ, Unverferth K, Grunwald C, Hartenhauer H, Heinecke K, Bernoster K et al. New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity. Eur J Med Chem 2007;42:873-79.
  18. Husain A, Alam MM, Zaman MS, Ahuja P. Synthesis and biological evaluation of 2-[3-(4-methoxy phenyl)propan-3-one]-5-(substituted phenyl)-1,3,4-oxadiazoles. Indian J HetrocyclChem 2008;17:265-66.
  19. Rajak H, Gupta AK, Kharya MD, Mishra P. Synthesis and antimicrobial activity of new 2,5-disubstituted 1,3,4-oxadiazoles. Indian J HetrocyclChem 2009;19:25-28.

9. / SIGNATURE OF THE STUDENT
10. / REMARK OF THE GUIDE
The above mentioned 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.
11. / 11.1 NAME AND DESIGNATION OF THE GUIDE
11.2 SIGNATURE / Sri. S. S. PUROHIT M. Pharm. , Ph.D.,
Lecturer
DEPT. OF PHARMA - CHEMISTRY,
SET’s COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD- 580002.
11.3 NAME AND DESIGNATION OF CO-GUIDE
11.4 SIGNATURE / ------
11.5 HEAD OF THE DEPARTMENT
11.6 SIGNATURE / Dr. S. D. JOSHIM.Pharm, Ph.D.
PROFESSOR AND HEAD
DEPT. OF PHARMA - CHEMISTRY,
SET’s COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD- 580002.
12. / 12.1 REMARK OF THE PRINCIPAL
12.2 SIGNATURE / The above mentioned information is correct and I recommend the same for approval.
Dr. V.H. KulkarniM.Pharm, Ph.D.
PROFESSOR & PRINCIPAL,
Set’sCollege of Pharmacy,
S.R.NAGAR, DHARWAD- 580002.