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SYNTHESIS AND EVALUATION OF MERCAPTO OXADIAZOLE DERIVATIVES OF BIOLOGICAL INTEREST
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, KarnatakaBangalore – 560041
By
Mr. DHADUK KAMLESH GHANSHYAMBHAI B.Pharm
Under the Guidance of
SRI. S. S. PUROHIT M. Pharm, (Ph.D.)
LECTURER,
DEPT. OF PHARMACEUTICAL CHEMISTRY,
Department of Pharmaceutical Chemistry
SET’s College of Pharmacy, S. R. Nagar, Dharwad,
Karnataka -580002
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
ANNEXURE –II
PROFORMA FOR REGISTRATION OF SUBJECT DISSERTATION
1. NAME OF THE CANDIDATE AND ADDRESS
MR. DHADUK KAMLESH GHANSHYAMBHAIDEPT. OF PHARMA CHEMISTRYSET’s COLLEGE OF PHARMACYS.R.NAGAR, DHARWAD- 580002.
2. NAME OF THE INSTITUTION SET’s COLLEGE OF PHARMACYS. R. NAGAR,DHARWAD- 580002.
3. COURSE OF STUDY AND SUBJECT
MASTER OF PHARMACY IN PHARMACEUTICAL CHEMISTRY
4. DATE OF ADMISSION TO THE COURSE
23-06-2011
5. TITLE OF THE TOPIC:
SYNTHESIS AND EVALUATION OF MERCAPTO OXADIAZOLE
DERIVATIVES OF BIOLOGICAL INTEREST.
6.0 BRIEF RESUME OF THE INTENDED WORK: 6.1 Need 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 names1. Azoles are five
membered heterocyclic compounds containing in their rings one or more hetero atoms, 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.3 Five membered heterocycles 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,18 muscle relaxant,4 antiviral,5 analgesic,6 anti-
cancer,19 anticonvulsant,20 anti-inflammatory,21 hypotensive,7 antimicrobial,22
anthelmintic,8 properties. Substituted mercapto oxadiazoles possess antimicrobial9,10,15,16,
antitubercular12, antifungal9,11,13, antitumor14 properties.
So, there is an urge to synthesize more potent derivatives containing these atoms
and this research is an attempt to synthesize better, effective substituted mercapto
oxadiazoles.
6.2 Review 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 Substituted mercapto oxadiazole
derivatives of pharmacological importance.
1. Shaharya M. et.al., have reported Oxadiazole mannich bases: Synthesis and
antimycobacterial activity.15
R1=C6H5 , R2=Furfuryl
R1=C6H5, R2=phenyl
2. Islam M. et.al., have reported synthesis and antimicrobial activity of some novel
oxadiazole derivatives.10
R=Phenyl, m-Xyly, P-tolyl, P-Chlorophenyl
3. Pattan SR. et.al., have reported Synthesis and evaluation of some novel
substituted 1,3,4,Oxadiazole and pyrazole derivatives for anti-tuberculer
activity.12
4. Jiao QC. et.al., have reported Synthesis, biological evaluation, and molecular
docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole
moiety as potential antitumor agents.14
R=2me-C6H4, 4-F-C6H4, 4NH2-C6H4
5. Mayekar AN. et.al., have reported Synthesis and Antimicrobial Studies on New
Substituted 1,3,4-Oxadiazole Derivatives Bearing 6-Bromonaphthalene Moiety.16
6. Parikh PK. et.al., have reported synthesis and biological evaluation of 1,3,4-
oxadiazole derivatives as potential antibacterial and antifungal agents.9
.
7. Kaplancikli ZM. et.al., have reported Synthesis of Some Oxadiazole
Derivatives as New Anticandidal Agents.11
R=P-Cl, m-Cl, H
8. Xu W. et.al. have reported Synthesis and Antifungal Activity of Novel
Sulfone Derivatives Containing 1,3,4-Oxadiazole Moieties.13
6.3 Objectives of Study:
1) To synthesize a new series of substituted mercapto oxadiazole derivatives of
highest purity.
2) To characterize the structure of the newly synthesized compounds by different
analytical techniques such as IR, NMR and Mass spectral data.
3) To evaluate the synthesized compounds for different biological activities.
7.0
MATERIALS AND METHODS:
7.1 Source 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.
World 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.17
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, Bacillus subtilis) and Gram-negative bacteria (Klebsiella
pneumoniae, 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 37 oC for 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.23,24
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, Aspergillus niger and Aspergillus flavus 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 broth
will 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 Aspergillus niger, Aspergillus flavus in 37 oC. The inoculum
sizes contained approximately 1105 cells/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
8.0
LIST OF REFERENCES:
1. http://www.3rd1000.com/chem301/chem302a.htm
2. http://prr.hec.gov.pk/Chapters/206-1.pdf
3. Alagwadi KR, Suresh S, Pattan SR, Pujar GV, Javali MC. Synthesis and
antimicrobial evaluation of some 2-substituted oxadiazoles. Indian J heterocycl
Chem 2007;17:93-94.
4. 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. Acta Chim slov 2007;54:317-24.
5. 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 Chem Lett 2004;14:4651-54.
6. 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 Heterocycl
Chem 2001;10:253-60.
7. Tyrkov AG, Tyurenkov IN, Timchenko MV, Perfilova VN. Hypertensive
activity of 3-aryl-5-nitromethyl-1,2,4-oxadiazoles and their alkyl substituted
derivatives. Pharm Chem J 2006;40:240-42.
8. 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 Heterocycl Chem 2009;18:321-24.
9. 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 & Research 2011;3(2):248-255.
10. Islam M, siddiqui AA, Ramadoss R, Bhakt A, Goyal S, synthesis and
antimicrobial activity of some novel oxadiazole derivatives. Acta Poloniae
Pharmaceutica n Drug Research 2008;65(4):441-447.
11. Kaplancikli ZA, Synthesis of Some Oxadiazole Derivatives as New Anticandidal Agents. Molecules 2011;16:7662-7671.
12. 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.
13. 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. Molecules 2011;16: 9129-9141.14. Jiao 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.
15. Shaharyar M, Ali MA, Oxadiazole mannich bases: Synthesis and
Antimycobacterial activity. Bioorg. Med. Chem. Lett 2007.
16. 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.
17. Talath S, Gadad AK. Synthesis, antibacterial and antitubercular activities of
some 7-[ 4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-piperazin-1-yl] fluoroquino-
lonic derivatives. Eur J Med Chem 2006;41:918-24.
18. Chaudhari BR, Shinde DB, Shingare MS. Synthesis of some 1,4-benzothiazinyl
thiosemicarbazides, triazoles, oxadiazoles, thiadiazoles and their antitubercular
activity. Indian J Heterocycl Chem 1995;4:187-90.
19. 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.
20. 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.
21. 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 Hetrocycl Chem 2008;17:265-66.
22. Rajak H, Gupta AK, Kharya MD, Mishra P. Synthesis and antimicrobial activity
of new 2,5-disubstituted 1,3,4-oxadiazoles. Indian J Hetrocycl Chem 2009;19:25-
23. Ryu CK, Park RE, Ma MY, Nho JH. Synthesis and antifungal activity of 6-
arylamino-phthalazine-5,8-diones and 6,7-bis(arylthio)-phthalazine-5,8-diones.
Bioorg Med Chem Lett 2007;17:2577–80.
24. Mcginnis MR, Rindali MG, Lorian EV, editor. Antibiotics in Laboratory
Medicine. 4th ed. Baltimore (USA): Williams and Wilkins; 1996. p. 176.
9. SIGNATURE OF THE STUDENT
10. REMARK OF THE GUIDEThe 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.), LecturerDEPT. 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. JOSHI M. 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. KULKARNI M. Pharm, Ph.D. PROFESSOR & PRINCIPAL, SET’s COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD- 580002.
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