SYNTHESIS AND BIOLOGICAL EVALUATION OFSOME NEW OXADIAZOLE ANALOGUES
PROTOCOL FOR
M. PHARM DISSERTATION
SUBMITTED TO
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,
KARANATAKA, BANGALORE
BY
VAISHALI SALUNKHE B.Pharm.,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
2010-2011
UNDER THE GUIDANCE OF
Dr. SENTHIL KUMAR. G.P., M.Pharm., Ph.D.,
PROFESSOR AND HEAD,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,
BHARATHICOLLEGE OF PHARMACY,
BHARATHI NAGARA,
KARNATAKA-571422.
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,
KARNATAKA,BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidate and Address / PRESENT ADDRESSVAISHALI SALUNKHE
I M. PHARMACY,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,
C/O BHARATHICOLLEGE OF PHARMACY,
BHARATHI NAGARA,
MANDYA (DIST),KARNATAKA-571422.
2. / Name of the Institution / BHARATHICOLLEGE OF PHARMACY,
BHARATHI NAGARA, MANDYA- 571422.
3. / Course of Study and Subject / MASTER OF PHARMACY IN PHARMACEUTICAL CHEMISTRY
4. / Date of Admission of Course / 27-07-2010
5. / Title of Topic / SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NEW OXADIAZOLE ANALOGUES
6. / Brief Resume of the Intended Work
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study / ENCLOSURE-I
7 /
Materials and Methods
7.1 Source of data
7.2 Method of collection of data
7.3 Does study require any investigations
or interventions to conducted on patients
or other human or animal? If so,
please describe briefly.
7.4 Has ethical clearance been obtained
from your institution in case of 7.3
/ ENCLOSURE-II8 / List of References / ENCLOSURE-III
9.
10.
11.
12. /
Signature of the candidate:
(Vaishali Salunkhe)
Remarks of the guide: This work will be carry out incollege laboratory.
11.1 Name And Designation of Guide: Dr. SENTHIL KUMAR G.P.,
PROFESSOR AND HEAD,
Department of Pharmaceutical Chemistry,
BharathiCollege of Pharmacy,
Bharathinagar,
Karnataka-571422.
11.2 Signature
11.3 Co-Guide ----
11.4 Signature
11.5 Head of the department Dr. SENTHIL KUMAR G.P.,
PROFESSOR AND HEAD,
Department ofPharmaceutical Chemistry,
BharathiCollege of Pharmacy,
Bharathinagar,
Karnataka-571422.
11.6 Signature
12.1 Remarks of the Chairman and Principal:
Forwarded For Approval
Dr. T. TAMIZH MANI,
PRINCIPAL,
BharathiCollege of Pharmacy,
Bhrathinagara,
Karnataka-571422.
12.2 Signature
ENCLOSURE-I
6. BRIEF RESUME OF INTENDED WORK:
6.1NEED FOR STUDY:
In the family of heterocyclic compounds, nitrogen containing heterocycles with an oxygen atom are considered as important class of compounds in medicinal chemistry because of their interesting diversified biological activities.During the past years considerable evidence have also accumulated to demonstrate efficacy of 1,3,4 oxodiazole including antimicrobial2,3,4, anti-inflammatory2,7, antimalarial, antitubercular5,16, antihypoglycemic, anticancer14,17, antiviral14, anticonvulsant and insecticidal12 properties. In addition, 1,3,4-oxadiazole have played a crucial part in the development of theory in heterocyclic chemistry and also used extensively in organic synthesis
Due to interesting activity of 2,5 disubstituted 1,3,4 oxodiazole as a biological agents considerable attention as been focused on this class. The pharmaceutical importance of these compounds lies in the fact that they can be effectively utilizing as antibacterial, antitubercular and insecticidal agents.
General structure
1,3,4 oxadiazole
In spite of the availability and accessibility of many existing antimicrobial drugs,most of them have adverse effects along with the pharmacological activity. In order to detect this, drug with good pharmacological activity and less side effects is required. Therefore, the present investigation comprises synthesis of some new oxadiazole derivatives and to evaluate their biological activities such as antimicrobial and anti-inflammatory activities.
REVIEW OF LITERATURE
Mogilaiah et al1., have beensynthesized of 1,3,4-oxadiazolyl-1,8-naphthyridines using iodobenzene diacetate in solid state. A simple and highly efficient procedure has been described for the synthesis of 1-(5-aryl-[1,3,4]-oxadiazole-2-yl-methyl)-3-(3-methylphenyl)-1H[1,8] naphthyridin-2-ones by the oxidation of the corresponding [2-oxo-3-(3-methylphenyl)-2H-[1,8]naphthyridin-1-yl]acetic acid arylidenehydrazides with iodobenzene diacetate [ph(OAc)2 in solid state.
Ar=C6H5
Vagdevi et al2., have been synthesized, antmicrobial and anti-inflammatory activities of 1,3,4-oxadiazole linked to naphthol[2,1-b]furan. Condensation of naphtha[2,1-b]furan-2-carboxyhydazide with different aromatic aldehydes afford the corresponding N1-[(1E)-arylmethylene]-naphthol[2,1-b] furan-2-carboxyhydrazides. These compounds undergo cyclization with acetic anhydride and mercuric oxide to yield 3-acetyl-5-naphthol [2,1-b] furan-2-yl-2-aryl-2,3-dihydro-1,3,4oxadiazole and 2-naphthol [2.1-b] furan-2-yl-5-aryl-1,3,4-oxadiazole, respectively. The compounds on refluxing with carbon disulphide and ethanolic potassium hydroxide followed by acidification with hydrochloric acid furnishes 5-naphtho[2,1-b]furan -2-yl-1,3,4-oxadiazole-2(3H)-thione. It is converted into Mannich base 3-(anilinomethyl)-5-naphthol [2,1-b]furan-2-yl-1,3,4oxadiazole-2(3H)thiones on treatment with formaldehyde and appropriate aromatic amines.
R=p-ClC6H4
Sunilet al3., have been synthesis and antimicrobial activity of some oxadiazole derivatives containing quinoline moiety. 2-[(2-methyl quinolin-8-yl)] acetohydrazide was condensed with different aromatic aldehydes to give arylidene derivatives which on cyclization in the presence of yellow mercuric oxide and iodine yielded a new series of 1,3,4-oxadiazole.Most of the compounds tested have shown promising antibacterical antifungal activity.
Khadaret al4., Microwave assisted synthesis of 1,3,4-oxadiazole carrying benzimidazole moiety and their antimicrobial properties. A new series of 2-substitued-1-[5-substitued phenyl-1,3,4-oxadiazol-2-yl)methyl]-H benzimidazole have been synthesized. The synthesized compounds were screened for their antibacterial and antifungal studies. Compound which contain benzyl group at 2-position of the benzimidazole moiety increases the both antibacterial and antifungal activity.
R1=Benzyl & R2=H ,R2=Cl,R2=Br,R2=Me,R2=OMe
Pattan et al5., have been synthesized and evaluation of some novel substituted 1,3,4-oxadiazole and pyrazole derivatives for antitubercular activity. The antitubercular screening was carried out by Middle Brook 7H9 agar medium against H37Rv strain. All the compounds have shown promising antitubercular activity.
R Ar R1
Chaudhari and Pai6., have been reported synthesis of biologically active 4-coumarin-6-yl(amino)-5-coumarin-3-yl-3-phenyl-1,2,4-oxadiazolines. Reaction of Schiff bases and hydrazones with benzhydroxamyl chloride respectively affored the corresponding 4-coumarin-6-yl-(amino)-5-coumarin-3-yl-3-phenyl-1,2,4-oxadiazoline. The newly synthesized compounds were screened for their antibacterial activity.
R1= H, R2= Cl, R3=CH3 R4= OCH3
Kitturet al7., reported synthesis and evaluation of some novel substituted 1,3,4-oxadiazole and pyrazole derivatives for antiinflamatory activity. Isonicotinic acid hydrazide showed potent anti-inflammatory activity.These compounds have shown promising anti-inflammatory activity when compared with the standard drug Diclofenac sodium.
Mogilaiah Ket al8.,Facile and efficient synthesis of 1,3,4-oxadiazolyl 1,8-naphthyridines under microwave irradiation.An efficient and convenient method for synthesis of 1-(5-aryl-[1,3,4]oxadiazol-2-ylmethyl)-3-(3-trifluromethyl-phenyl-1H-[1,8]naphthyridin-2-ones,by the oxidation of [2-oxo-3-(3-trifluoromethyl-phenyl)-2H-[1,8]naphthyridin-1-yl]acetic acid arylildenehydrazideswith iodobenzene diacetate under microwave irradiation in solvent free condition.
Ar = C6H5, p-CH3C6H4.
Shailajaet al9., have been synthesized and biological activity of novel 2,5-disubstituted-1,3,4-oxadiazoles.The derivatives are synthesized starting from substituted pyridinyloxy benzaldehydes,by converting them in to corresponding arylidene hydrazides followed by chloramine.
Iqbalet al10., have been synthesized,antimicrobial and anti-HIV activity of some novel benzenesulfonamides bearing 2,5-disubstituted-1,3,4-oxadiazole moietyprepared by direct chorosulfonation of phenyl substituent present on the 2-position of 5-mercapto-1,3,4-oxadiazoles their methylthio derivatives using chlorosulfonic acid under anhydrous condition
R=H,R=OCH3,R=Cl
Dai et al11., reported a new route of synthesis of 3,6-diaryl-1,2,4-triazolo[3,4-b]1,3,4-oxadiazoles.Five new 3,6-diaryl-1,2,4-triazolo[3,4-b]1,3,4-oxadiazole derivatives were synthesized by 9 steps from aromatic acids and evaluated for their anticancer and antibacterical.
R=4-Br-Ph,R1=Ph
Shiet al12., 1,3,4-oxadiazole is among very few pharmacophore known for it insecticidal activity. A novel series 2-fluorophenyl-5-aryl/cyclopropyl-1,3,4-oxadiazoles were evaluated for their insecticidal potential.
R= 3-fluorophenyl, 2,4-dichloro-5-fluorophenyl, R1= 2-chloro-3-pyridyl, 6-chloro-3-pyridyl
Othmanet al13., reported the synthesis of 1,3,4-oxadiazole and 1,2,4-triazole derivatives and investigated antibacterial activity against E.coli, S. aureus and P. aeruginosa.
Hameed et al14.,have been synthesize new benzothiazole derivatives bearing amido-mercapto substituted 1,3,4-oxadiazoles and to investigate their antiviral activity.
R= Br, Cl, CH3 and R1= CH3, C2H5.
Kidwai et al15.,synthesized 1,3,4-thiadiazolyl substituted 1,3,4-oxadiazole using microwave showing antifungal activity against A. niger and A.flavous.
R -4CH3 or R -2-Cl
Shahar et al16., they have synthesized and evaluated the anti-tuberculostic activity of novel 1,3,4-oxadiazole derivatives against M. tuberculosis.
R1= C6H5, R2= C6H5OCH2, 3-Cl-C6H4.
Aboraia et al17., have synthesized novel 5-[2-(2-halobenzyloxy) phenyl]-1,3,4-oxadiazoles and it is having invitro anticancer activity against various cancer cell lines.
R= 1-morpholine, 1- phenylpiperazine.
OBJECTIVES:
1,3,4-oxadiazole derivatives have attracted attention owing to their effective biological activity and extensive use. There are several methods available in literature for the synthesis of 1,3,4-oxadiazole. However, some of these methods suffer from disadvantages such as long reaction time, low yield, requirement of severe conditions and using strong or toxic or costly reagents. Therefore, synthesis of new derivatives with greater efficacy and better yield still is desirable.
During the past decades, the human population affected with life-treating infectious diseases caused by multi-drug resistant Gram-positive and Gram-negative pathogen bacteria increased an alarming level around the world. Due to this reason, new classes of antibacterial agents with novel mechanisms are crucial need to combat with the multidrug resistant infections. Most of the aryl alkanoic acids showed potent anti-inflammatory activity but the major side effect of aryl alkanoic acid is their gastric irritation, which is partly due to the corrosive nature of carboxylic acid group present in them. So in order to mask the side effects of carboxylic moiety we planned to synthesize various 2,5-disubstituted-1,3,4-oxadiazole derivatives via the condensation of various arylo hydrazide with various aromatic or aliphatic acids in presence of phosphoryl chloride and to evaluate their biological activities such as antimicrobial and anti-inflammatory activity.
Based on the literature, the main objective of the present study deals with,
To establish the method of synthesis for the proposed compounds.
To synthesize the title compounds by appropriate methods.
To carry out the preliminary tests such as physical constant determination, solubility, TLC.
To confirm the structures of the synthesized compounds by IR,1H-NMR, 13C-NMR, Mass spectra, CHN analysis calculated.
To evaluate the proposed compounds for their antimicrobial and anti-inflammatory activity.
ENCLOSURE-II
7. METHODOLOGY:
7.1SOURCE OF DATA:
1.The literature survey will be done by referring chemical abstracts of all the National and International Journals pertaining to Synthetic, Medicinal and Pharmaceutical chemistry.
2.The information about pharmacological and biological activities will be collected by referring Journals of Current Pharmaceuticals Research, International Journal of Pharmaceuticals and Biomedical Research, Journals of Medicinal Chemistry, etc.
3.Library of Bharathi College of Pharmacy, Bharathinagara, Indian Institute of Science, Bangalore, IICT Hyderabad, IIT Chennai.
4.The day to day development in this area will be updated by literaturesurveythrough E-publishing & current periodicals in library of Bharathi College of Pharmacy, Bharathinagara.
5.All the basic facilities required for synthetic pharmaceutical chemistry are available in laboratories of Bharathi College of Pharmacy, Bharathinagara. For purification of the products TLC, other facilities are also available in Bharathi College of Pharmacy Laboratories.
7.2METHOD OF COLLECTION OF DATA
The chemical structure of the synthesized compounds will be established on the basis of physical, chemical and analytical data. Melting points of the synthesized compounds were determined by open capillary and are uncorrected. The purity of the synthesized compounds was checked by TLC using silica gel.
The synthesized compound will be characterized by 1H-NMR, 13C-NMR and Mass spectral data. This will be collected by sending the sample to other advanced research centers like IISC Bangalore, IICT Hyderabad & IIT Chennai. All the molecules will be screened for their pharmacological activities in our laboratory.
7.3 Does the study require any investigation or interventions to beconducted on patients or other humans or animals?
Yes
7.4Has ethical clearance been obtained from your institution in caseof 7.3?
Yes, attached institutional ethical clearance certificate.
ENCLOSURE-III
8. REFERENCES:
- Mogilaiah K,Shiva Kumar K,Kumar Swamy J. Synthesis of 1,3,4-oxadiazolyl-1,8-naphthyridines using iodobenzene diacetate in solid state.IndianJ Chem 2010;49B:840-4.
- Ravindra KC, Vagdevi HM, Vaidya VP,Basavaraj , Padmashali. Synthesis antimicrobial and anti-inflammatory activities of 1,3,4-oxadiazoles linked to naphthol[2,1-b]furan.IndianJ Chem 2006;45B:2506-11.
- Sunil Kumar Chaitanya P,Ishwar Bhat K,Irfan Ali MD.Synthesis and antimicrobial activity of some oxadiazole derivatives containing Quinoline moiety.J Pharm Chem 2009;3:19-22.
- Janardhana Gowda, Khadar AM,Balakrishna Kalluraya,Nalilu Kumari.Microwave assisted synthesis of 1,3,4-oxadiazole carrying benzimidazole moiety and their antimicrobial properties. IndianJ Chem 2010;49B:1130-4.
- 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 antitubercular activity. IndianJ Chem 2009;48B:1453-6.
- Chaudhari SP andPai NR.Synthesis of biologiclly active 4-coumarin-6-yl(amino)-5-coumarin-3-yl-3-phenyl-1,2,4-oxadiazolines. IndianJ Chem 2009;48B:286-90.
- Kittur BS, Sastry BS, Pattan SR, Rabara PA, Pujari RW, Wakale VS.Synthesis and evaluation of some novel substituted 1,3,4-oxadiazole and pyrazole derivatives for anti-inflammatory activity.Ind Drugs 2009;46(5):403-8.
- Mogilaiah K.Facile and efficient synthesis of 1,3,4-oxadiazolyl 1,8-naphthyridines under microwave irradiation. IndJ Chem 2009;48B:868-72.
- Shailaja M,Anitha M,Manjula A, Rao BV.Synthesis and biological activity of novel 2,5-disubstituted-1,3,4-oxadiazole.Indian J Chem 2010;49B:1088-97.
- Iqbal R,Zareef M,Ahmed S,Zaidi JH,Arfan M,Shafique M,Masoudi AL.Synthesis, antimicrobial and anti-HIV activity of some novel benzenesulfonamides bearing 2,5-disubstituted-1,3,4-oxadiazole moiety. J Chin Chem Soc 2006;53:689-96.
- Chao-Feng-Dai, Shu-Jun-Chao,Peng-Fei-Xu,Zi-Xi-Zhang.A New Route to Synthesis of 3,6-diaryl-1,2,4-triazolo[3,4-b]1,3,4-oxadiazole. J Chin Chem Soc 2004;51:1343-6.
- Shi W, Qian X, Song G, Zhang R, Li R. Synthesis and insecticidal activities of novel 2-fluorophenyl-5-aryl/cyclopropyl-1,3,4-oxadiazoles.J Fluorine Chem 2000;106:173-9.
- Othman AA, Khiati Z, Guessas BS. Synthesis of 1,3,4-oxadiazole and 1,2,4-triazole and screening of their pharmacological activity. Afr J Chem 2007;60: 20-4.
- Tashfeen Akhtar, Shahid Hameed, Najim A, Al-Masoudi, Roberta Loddo, Paolo La Colla.In vitro antitumor and antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives. Acta Pharm 2008;58:135-49
- Kidwai M, Goel Y, Kumar P. Microwave assisted synthesis of new bioactive 1,3,4-thidiazolyl substituted 1,3,4-oxadiazole. Ind J Pharm Sci 1998;60:396-8.
- Shahar M Yar, Ahmad Siddiqui A, Ashraf Ali M. Synthesis and antituberculostatic activity of novel 1,3,4-oxadiazole derivatives. J Chin Chem Soc 2007;54:56-8.
- Ahmed S Aboraia, Hamdy M, Abdel Rahman, Nadia M Mahfouz, Mahmoud A,EL-Gendy.Novel5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives promising anticancer agents. Bio org Med Chem 2006;14:1236-8.