“STUDIES ON THE SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF SOME NEW SUBSTITUTED IMIDAZOLES”
M.PHARM DISSERTATION PROTOCOL
SUBMITTED TO
Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka
By
PENDBHAJE NILESH SANJAY
UNDER THE GUIDANCE OF
Dr. G.K. KAPSE
M.Pharm Ph.D.
Professor
POST GRADUATE DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
LUQMAN COLLEGE OF PHARMACY, GULBARGA-585102.
2011-12
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the candidate Andaddress / PENDBHAJE NILESH SANJAY
Luqman college of pharmacy,
old jewargi road,
gulbarga-585102
2. / Name of the institution / Luqman college of pharmacy,
old jewargi road,
gulbarga-585102
3. / Course of study and subject /
master of pharmacy
(Pharmaceutical Chemistry)
4. / Date of Admission of course / Nov2011
5. / Title of the Topic:
“STUDIES ON THE SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF SOME NEW SUBSTITUTED IMIDAZOLES”
6.
6.1
6.2 / Brief Resume of the intended work:
Need for study:
The chemistry of heterocyclic compounds in the field in the organic chemistry which is being explored continuously. The importance of substituted imidazole derivatives lies in the field that, these derivatives represent one of the most biologically active classes of compounds, possessing a wide range of therapeutic properties.
Imidazole (1,3-diaza-2,4-cyclopentadiene) is a vital heterocyclic nucleus which has been extensively studied from past few years in the field of drug research. The wide range of therapeutic properties encourages the medicinal chemists to synthesize more number of therapeutic agents. Imidazoles display wide array of pharmacological activities such as anthelmintic, anticancer, antimicrobial, antifungal and anti-inflammatory, antifungal. As it is a polar and ionisable aromatic compound, it magnifies the pharmacokinetic properties of lead molecules and thus served as a remedy to optimize the solubility and bioavailability parameters of proposed poorly soluble lead molecules[1,2].
The above mentioned reports encouraged us to modify 2,4,5-trisubstituted imidazoles into various bioactive structures. Hence, in the present proposal, we would like to synthesize substituted imidazoles with the help of Claisen Schmidt reaction by using various substituted aldehydes.
Review of Literature:
Abundant references are available with regarding the study of 2,4,5-trisubstituted
Imidazoles. The literature survey reveals that the compound containing 2,4,5-
trisubstituted imidazoles are reported to possess diverse biological activities. Few
important are as below:
· Kumari Shalini et al (2010) reported in the Imidazole and its biological activities: A review, Anti fungal , Anti-bacterial activity, Anti inflammatory activity, analgesic activity, Anti tubercular activity, Anti-depressant activity, Anti-cancer activity, Anti-viral activity, Antileishmanial activity[3].
· Mohd Sajid Khan et al (2008) synthesized some novel 2,4,5-trisubstituted imidazole derivatives and evaluated for in-vitro antibacterial activity against strain of Klebsiella pneumonia using tube dilution method[4].
· Bakr F. Abdel-Wahab et al (2011) synthesized some new imidazole-based heterocycles and screened for variety of activity like antimicrobial, antioxidant, anti-hemolytic and cytotoxic evaluation [5].
· Dae-Kee Kim et al (2008) have synthesized and biologically evaluated some trisubstituted imidazole derivatives as inhibitors of p38a mitogen-activated protein kinase[6].
· Sanchita Baroniya et al(2010) reported the Recent advancement in imidazole as anti-cancer agents[7].
· Jianjun Chen et al (2011) reported the synthesis and ant proliferative activity of novel 2-aryl-4-benzoyl-imidazole derivatives targeting tubulin polymerization[8].
· Daniele Zampieri et al synthesized the imidazole derivatives antifungal and antimycobacterial activities against two clinical isolates of Candida albicans 3038 and Candida glabrata 123[9].
· Xiao-Dong Yang et al(2012) reported the cytotoxic activity of synthesized imidazole compounds against a panel of human tumor cell lines[10].
· ASIF HUSAIN et al (2009) synthesized and reported the anti-inflammatory and antimicrobial actions of di and tri substituted imidazoles by carrageenan induced rat paw edema test with very low ulcerogenic activity and against fungal species respectively[11].
· A.Yasodha et al (2009) synthesized and reported the anti-inflammatory, antimicrobial
activities. The antimicrobial activity was carried out with the help of carrageenan induced
rat paw oedema method and antimicrobial activity was screened by disc-plate method[12]
· D. D. Bhragual et al (2010) synthesized and reported anticonvulsant activity.The anticonvulsant activity is evaluated by Maximal Electroshock Method (MES)[13].
· Kalpana Bhandaria et al (2010) synthesized and reported antileishmanial activity of substituted aryloxy alkyl and aryloxy aryl alkyl imidazoles and evaluated in vitro againstLeishmania donovani[14].
6.3
7
7.1
7.2
7.3
7.4
7.4-1
7.5
7.6
8. / Objective of the study:
It is well established that various derivatives of substituted imidazoles exhibit broad
spectrum of pharmacological properties such as antibacterial and antifungal activities etc.
Many of the available therapeutically important medicines such as ketoconazole,
itraconazole, voriconazole and fluconazole contain this heterocyclic nucleus.
Prompted by these observations, we have planned to prepare some new 2,4,5-
trisubstituted imidazole and evaluate for their biological activities.
The present investigation includes:
· Synthesis of various derivatives of substituted 2,4,5-trisubstituted imidazole following literature method.
· The chemical structure of the compounds synthesized could be established on the basis of elemental analysis and IR, NMR and Mass spectral studies.
· The compound of the above type would be tested for antimicrobial activity against different strains of pathogenic organisms by following literature methods. Similarly, few of the selected compounds would also be screened for antidepressant activity using Forced Swimming Test .
Materials and Methods:
Method of collection of data:
· From available literature.
· From library based books
· Web sites
· www.sciencedirect.com.
· http://jgate-helinet.informindia.co.in
· www.pubmed.com.
· www.scirus.com.
· www.herbmed.com.
Synthetic strategy:
Various 2,4,5-substituted imidazoles will be synthesized by following literature methods[17].
Various derivatives will be synthesized by conventional synthetic strategy and their yield, physical constant and analytical profile will be determined. All the reactions will be monitored by TLC techniques and chemical tests wherever applicable.
Biological screening:
· Anti-microbial activity:-
All the compounds will be screened for antibacterial activity and antifungal activity using Cup & Plate method in our laboratory and the activities will be compared with the known standard anti-microbial agents[18] .
· Anti-depressant activity : Forced swim test in rats :-
This test is the modification of the method of Porsolt and others. Unlike Porsolt’s method for mice which consists of direct immersion of animals after injecting the drugs, the mice are subjected to ‘pre test session’ for 15 minutes in a glass cylinder (21*12*12) containing water up to a height of 9cm maintained at 25+2oC.Twenty four hours later, the animals were treated intraperitoneally with the test compounds and Fluoxetine and each animal is again forced to swim in similar environment for a period of 6 minutes in a test session and immobility was recorded. The mouse was judged immobile if it ceased struggling and remained floating motionless in water[19].
· Group-I Animals (Control).
· Group-II Animals (standard drug) fluoxetine 20mg/Kg.
· Group-Ш onwards (test compounds) for each compound.
Source of data:
The present investigation includes the synthesis of target molecules and the newly synthesized molecules will be characterized to generate the data as follows:
· The reactions will be monitored by TLC technique and Rf values will be recorded; Percentage of yield for each reaction will be determined.
· The physical constant, solubility and elemental analysis will be carried out for newly synthesized compounds.
· IR, NMR and Mass spectral data will be obtained for newly synthesized compounds to elucidate their structures.
Biological Activity:
· Antimicrobial (antibacterial & antifungal) screening of compounds can be done by Cup and Plate method and zone of inhibition for each compound at 50μg/ml and 100μg/ml will be recorded and the activity will be compared with that of the standard.
Pharmacological activity:
· Pharmacological screening for Antidepressant activity of the compounds can be done by forced swim test and the duration of immobilization is to be recorded and can be compared with standard [19].
· Assessment of toxic effect: As per OECD-425 guidelines.
Screening of Statistical analysis:
Data are expressed as mean ± S.E.M. Results of in vivo tests were compared by
ANOVA followed by Dunnett’s ‘t’ test.
Does the study require any investigations or interventions to be conducted on patients or humans or animals? If so, please describe briefly.
Albino rats and mice of Wistar strain will be used for the evaluation of anti-inflammatory activity and analgesic activity.
Has ethical clearance been obtained from your institution in case of 7.3?
The present study is approved from Institutional Animal Ethics Committee (IAEC copy enclosed).
List of References:
1. Bhatnagar A, Sharma P. K, Kumar N, A Review on “Imidazoles”: Their Chemistry
and Pharmacological Potentials, International Journal of PharmTech Research, Jan-Mar
2011, Vol. 3, No.1, pp 268-282.
2. The Merk Veterinary Manual, 2011.
3. Kumari Shalini,Pramod Kumar Sharma, Nitin Kumar, Imidazole and its biological activity, Der Chemica Sinica, 2010, 1 (3): 36-47.
4. Mohd Sajid Khan1,4, Shafi Ahmad Siddiqui, Antibacterial Activity of Synthesized 2,4,5-Trisubstituted Imidazole Derivatives, Journal compilation ©2008 Blackwell Munksgaard Issue Chemical Biology & Drug Design, Volume 72, Issue 3, pages 197–204, September 2008.
5. Bakr F, Abdel Wahab ,Ghada E.A, Farid A. Badria, Synthesis,
antimicrobial, antioxidant, anti-hemolytic and cytotoxic evaluation of new imidazole-
based heterocyclic,2011 Elsevier Masson SAS.
6. Dae-Kee Kim, Jin-Hwi Lim, Jung A. Lee, Purushottam M. Dewang Synthesis and biological evaluation of trisubstituted imidazole derivatives as inhibitors of p38a mitogen-activated protein kinas, Bioorganic & Medicinal Chemistry Letters 18 (2008) 4006–4010
7. Sanchita Baroniya, Zaihra Anwer, Pramod K. Sharma, Rupesh Dudhe, Nitin Kumar, Recent advancement in imidazole as anti-cancer agents: A review, Der Pharmacia Sinica, 2010, 1 (3): 172-182.
8. Jianjun Chen a, Chien-Ming Li b, Jin Wang a, Sunjoo Ahn b, Zhao Wanga, Yan Lu a, James T. Dalton b,Wei Li a,Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl-imidazole Bioorganic &Medicinal Chemistry journal,
9. Daniele Zampieri,a Maria Grazia Mamolo,Luciano Vio, Elena Banfi,b,Giuditta Scialino,b Maurizio Fermeglia,c Marco Ferronec and Sabrina Priclc, Synthesis, antifungal and antimycobacterial activities of new bis-imidazole derivatives, Bioorganic & Medicinal Chemistry 15 (2007) 7444–7458 .
10. Xiao-Dong Yang a, Wei-Chao Wana, Xiao-Yan Deng a, Yan Li b, Li-Juan Yang c, Liang Li a, Design, synthesis and cytotoxic activities of novel hybrid compounds between
2-phenylbenzofuran and imidazole, Bioorganic & Medicinal Chemistry Letters, 22 (2012)
2726–2729.
11. Asif Husain, Sushma Drabu and Nitin Kumar,Synthesis and biological screening of di and tri substituted imidazoles, Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 66 No. 3 pp. 243,248, 2009.
12. A.Yasodha, A.Sivakumar, G.Arunachalam, A.Puratchikody, Synthesis and evaluation of 2,4,5-trisubstituted imidazole derivatives, Journal of Pharmaceutical Science and Research Vol. 1 (4), 2009, 127-130.
13. D. D. Bhragual, N. Kumar1and S. Drabu, Synthesis and pharmacological evaluation of some substituted imidazoles, J. Chem. Pharm. Res., 2010, 2(2): 345-349.
14. Kalpana Bhandaria,Nagarapu Srinivasa,Vijay K. Marrapua, Aditya Vermab, Saumya Srivastavab, Suman Guptab, Synthesis of substituted aryloxy alkyl and aryloxy aryl alkyl imidazoles as antileishmanial agents,Bioorganic and medicinal chemistry letters,vol.20,Issue.1,January 2010,Page.291-293.
15. Bhatnagar A, Sharma P. K., Kumar N, A Review on “Imidazoles”: Their Chemistry and Pharmacological Potentials, International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304, Vol. 3, No.1, pp 268-282, Jan-Mar 2011.
16. Synthesis of Imidazoles, Alexandros Zografos.
17. Asif Husain, Sushma Drabu and Nitinkumar, Synthesis and Biological Screening of di and tri substituted imidazoles, Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 66 No.243-248, 2009.
18. Anisetti Ravinder Nath and MalladiSrinivas Reddy, Design, Synthesis, Antibacterial and Antifungal Activity of Novel 2-[(E)- 2-aryl-1-ethenyl]-3-(2- sulfanyl-1H-benzo[d]imidazole-5-yl)-3,4- dihydro-4- quinolinones, E-Journal of Chemistry, 2012, 9(3), 1481-1489.
19. Sanjay B.Kasture,A Handbook of Experiments in Pre-Clinical Pharmacology, Career Publications, first edition, Page no.64.
9. / SIGNATURE OF CANDIDATE / (PENDBHAJE NILESH SANJAY)
10. / REMARKS OF THE GUIDE / The candidate is working under my direct supervision in laboratories of L.C.P Gulbarga-585202
11. / NAME AND DESIGNATION OF11.1 GUIDE /
Dr. G. K. KAPSE M.Pharm Ph.D
PROFESSOR
11.2 SIGNATURE
11.3 CO-GUIDE (IF ANY) / Prof. G.SUDHEENDRA M Pharm. (Ph.D)
PROFESSOR
11.4 SIGNATURE
11.5 HEAD OF DEPARTMENT
11.6 SIGNATURE / Prof. G. SUDHEENDRA M Pharm. (Ph.D)
12. / REMARKS OF THE CHAIRMAN AND PRINCIPALRecommended and Forwarded12.1 SIGNATURE
(Principal)
2