Synthesis and Evaluation of Benzofuran Derivative

“SYNTHESIS AND EVALUATION OF BENZOFURAN DERIVATIVE

FOR THEIR

ANTI-MICROBIAL AND ANTI-INFLAMMATORY ACTIVITES”

M.PHARM DISSERTATION PROTOCOL

SUBMITTED TO

Rajiv Gandhi University of Health Science Bangalore, Karnataka

BY

ABHISHEK RAJ PACHORI

B.Pharm

UNDER THE GUIDANCE OF

Dr. SADATH ALI

M.Pharm Ph.D

ASST. PROFESSOR

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

LUQMAN COLLEGE OF PHARMACY, GULBARGA-585102

2009-2010

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1.  / Name of the candidate And
address / abhishek raj pachori
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 / 27.06.09
5. / Title of the Topic:
“SYNTHESIS AND EVALUATION OF BENZOFURAN DERIVATIVES FOR THEIR ANTIMICROBIAL AND ANTI-INFLAMMATORY ACTIVITES”
6. / Brief Resume of the intended work:
6.1 Need for the study:
Many important biochemical compounds and drugs of natural origin contain heterocyclic ring structures. The presence of heterocyclic structure in such different type of compounds is strongly indicative of the diverse pharmacological activities and recognition of this is reflected in efforts to find useful synthetic drugs.
The benzofuran ring system itself is a common structure element that appears in a large number of medicinally important compounds1. The benzofuran nucleus is widely distributed in natural products particularly among plant kingdom. In the chemistry of benzofurans in a large number of natural products has attracted due to their biological activities and their potential application as pharmacological agents2.
Various benzofuran derivatives possess different pharmacological and biological activities of which the most potent is anti-inflammatory3, pesticidal insecticidal4, antihistaminic5, anticonvulsant6, antiallergic7. In vitro-HIV-1, anticancer, anti-microbial activities8. The antimicrobial activity of benzofuran derivatives appears to be dependent on substitution at the heterocyclic furan ring than the aromatic moiety1.
The development of resistance to current anti-bacterial and anti-fungal therapy continues to stimulate the search for more effective agents. The increasing clinical importance of drug resistant bacterial and fungal pathogens has lent additional urgency to microbiological research and development of biologically more potent compounds.
Based upon the above reference the effort will be made to synthesize the substituted benzofuran derivative and screening them for anti-microbial and anti-inflammatory activities.
6.2 Review of Literature:
The extensive literature survey revealed that compounds containing benzofuran derivatives are reported to posses a wide range of biological activities and synthesis of these compounds which is clinically used as anti-microbial & anti- inflammatory substances. There are few literature review of Benzofuran are as under.
Ø  Gurubasavaraja P. M. et al., (2008)9
2-Acetyl-3-hydroxy benzofuran were allowed to react separately with different aromatic aldehydes in presence of 50% alkaline medium to yield the corresponding 3-hydroxy benzofuran substituted chalcones. The compounds obtained were identified by spectral data and screened for antimicrobial activity.
Ø  Goudarshivannanavar B. C. et al., (2009)10
A short of benzo[b]furo indolyls derivatives from 2-acetylbenzofuran in two steps and corresponding pyrazoles derivatives is described. An interesting scale-up procedure for the synthesis of 2-acetylbenzofuran is also been reported. Similarly 2-acetylbenzofurohydrazones derivatives are prepared from 2-acetyl benzofuran and with various phenylhydrazine hydrochlorides in presence of CH3COONa/EtOH at RT in excellent yield (90-95%). These 2-acetyl benzofurohydrazones derivatives are subjected to Fischer indole cyclisation in presence of ZnCl2 in acetonitrile as solvent to get 2(2-benzo[b]furo) indole derivatives good yield.
Ø  Koca Murat et al., (2005)11
Synthesis of (benzofuran-2-yl) (3-phenyl-3-methylcyclobutyl) ketoxime derivatives was carried out from the reaction with different amines, various halogen containing compounds. New derivatives of (benzofuran-2-yl) (3-phenyl-3-methylcyclobutyl) ketoxime such as O-glycidylketoxime, O-phenylacylketoxime were obtained very high yields. All the synthesized compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumonia ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis ATCC 14153 and Candida albicans ATCC 10231.
Ø  Podea Paula Veronica et al., (2008) 12
Lipase mediated DKR followed by a chemical and an enzymatic hydrolytic step were combined for the synthesis of enantiopure L-benzofuranyl- and L-benzothienyl alanines.
Ø  Basawaraj Raga et al., (2009)14
The reaction of 3-amino-2-benzofurancarboxamide1 with 3, 4, 5-trimethoxybenzaldehyde in presence of catalytic quantity of conc. hydrochloride acid gave 2-aryl-3,4-dihydro-4-oxobenzofuran[3,2-d] pyrimidine2. The nucleophilic displacement reaction of compound 2 with phosphorus oxychoride furnished 2-(3, 4, 5-trimethoxyphenyl)-3, 4-dihydro-4-chlorobenzofuro [3,2-d] pyrimidine3. Some 2, 4-disubstituted benzofuran [3,2-d] pyrimidine derivatives were prepared by the reaction of compound 3 with different reagents. All the synthesized compounds were characterized on the basis of IR, 1HNMR, mass spectra and analytical data. The compounds synthesized were screened for biological activities.
Ø  Basawaraj Raga et al., (2009)13
Michael condensation of 2-arylideneacetylbenzofurans derivatives with ethyl cyanoacetate and malononitrile afforded 4-aryl-6-(benzofuran-2’-yl) nicotinonitrile-2-ones derivatives and 2-amino-4-aryl-6-(benzofuran-2’-yl)-3-cyanopyridines derivatives, respectively. All the compounds showed good antimicrobial activity.
7. / 6.3 Objective of the study:
The increasing clinical importance of drug resistant bacterial and fungal pathogens has lent additional urgency to anti-microbiological research and development of new antibacterial, antifungal compounds. Hence, the necessary data will be generated by laboratory experimental techniques which includes :
Ø  Synthesis of substituted Benzofuran derivatives.
Ø  Characterization of the newly synthesized compounds by IR, NMR, Mass spectroscopy.
Ø  Anti-microbial and Anti-inflammatory activity of the synthesized compounds.
Materials and Methods:
7.1 Source of data:
The research work that will be carryout in the laboratory by various experimental technique includes:
1.  Synthesis of target molecules and determination of their physical constant, solubility, elemental analysis data will be done.
2.  Spectroscopic data of new compounds i.e. I.R., NMR, Mass will be done for structural confirmation of the synthesized compounds.
3.  Pharmacological screening for antimicrobial activity by Cup and Plate method and result will be compared with that of the standard10.
4.  Pharmacological screening for anti-inflammatory activity by carrageenan-induced edema in Rats compared with standard drug5.
Synthetic strategy:
The reaction of salicylaldehyde with 2-chloro propane-2-one and potassium hydroxide /potassium iodide / ethanol will be used to prepare 2-acetyl benzofuran for the starting basic benzofuran molecules. Compound 1 will be synthesized from the reaction of the 2-acetyl benzofuran with different substituted aldehydes in presence of 50% alkaline medium. After formation of Compound 1 different derivatives will be formed by substitution of different aromatic aldehydes.
Similarly new other derivatives will be prepared from compound 1 and with various phenylhydrazine hydrochlorides in presence of CH3COONa/ Et-OH.
Scheme:-
The various derivatives will be synthesized by conventional synthetic strategy and their yield, physical constant and analytical profile will be determined.
Spectroscopic data:
I.R., NMR, Mass data will be collected using commercial research center.
Biological screening:
1.  Anti-microbial activity:-
All the compounds synthesized will be subjected to screening against both gram positive (Staphylococcus aureus, Bacillus subtilis) and gram negative (Escherichia coli, Klebsiella pneumonia) bacteria and antifungal15 activity against (Candiada albicans, Aspergillus flavus) by using Cup & Plate method in our Laboratory and results will be compared with the known standard Anti- microbial agents16-17.
2.  Anti-inflammatory activity:-
a)  Carrageenan-induced edema in Rats:-
The method of Kamal M. Dawood et al., will be followed5:
In the dose response experiment, albino rats were randomly assigned into 8 groups of 6 each.
·  Group-I Animals (Control) were administered 1ml distilled water p.o.
·  Group-II Animals (standard drug) Ibuprofen 10mg/Kg was administered p.o.18
·  Group-III Animals were administered with first derivatives (selected low dose) p.o.
·  Group-IV Animals were administered with first derivatives (selected high dose) p.o.
·  Group-V Animals were administered with second derivatives (selected low dose) p.o.
·  Group-VI Animals were administered with second derivatives (selected high dose) p.o.
·  Group-VII Animals were administered with third derivatives (selected low dose) p.o.
·  Group-VIII Animals were administered with third derivatives (selected high dose) p.o.
7.2 Method of collection of data:
1.  From available literature.
2.  From library based books
3.  Web sites
-  www.sciencedirect.com.
-  http://jgate-helinet.informindia.co.in
-  www.pubmed.com.
-  www.scirus.com.
-  www.herbmed.com.
7.2-1 Elemental analysis:-
·  IR. Spectra studies.
·  NMR. Spectra studies.
·  Mass Spectra studies
7.2-2 Assessment of toxic effect:
As per OECD-425 guidelines.
7.2-3 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.
7.3 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 Wister strain will be used for the evaluation of anti-inflammatory activity.
7.4 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) and Ethical clearance obtained.
8. / List of References:
1.  Yoo S.E., Lee S. H. & Kim S.K., The Conformation and activity Relationship of benzofuran derivative as Angiotension II Receptor antagonist. Bioorg. Med. Chem, 1997; 5:445-459.
2.  Bakr F. Abdel-Wahab, Hatem A. Abdel-Aziz, Essam M. Ahmed, Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyrazoles. Eur. Journal of Med. Chem., 2009; 44:2632-2635.
3.  Santana L., Teijeira M., Uriarte E., Teran C., Linares B., Villar R., Laguna R., Cano E., AM1 theoretical study, synthesis and biological evaluation of some benzofuran analogues of anti-inflammatory arylalkanoic acids. Eur. J. Pharm. Sci., 1998; 7:161-166.
4.  John A. Findlay, Sentsetsa Buthelezi, Guoqiang Li, Michelle Seveck, Insect Toxin from an endophytic fungus from wintergreen. J. Nat. Prod., 1997; 60(11):1214-1215.
5.  Leonardi A., Nava G., Nardi D., Synthesis of benzofuran derivatives with H2 antagonist activity, Farmaco. Ed. Sci., 1983; 38(5):290-308.
6.  Kamal M.Dawood, Hassan Abdel-Gawad, Eman A. Rageb, Mohey Ellithey and Hanan A. Mohamad, Synthesis, anticonvulsant, and anti-inflammatory evaluation of some new benzotriazole and benzofuran-based heterocycles. Bioorg. Med. Chem., 2006; 14:3672-3680.
7.  Musser J.H., Brown R.E., Love B., Bailey K., Jones H., Kahen R., Huang F.C., Khandurala A., Leibowitz M., Sonniua-Goldman P., Donigi-Ruzza D., Synthesis of 2-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) benzo heterocycles. A novel series of orally active antiallergic agents. J.Med.Chem, 1984; 27:121-125.
8.  Samia M. Rida, Soad A. M. EI-Hawash, Hawash T. Y. Fahmy, Aly A. Hazzaa, and Mostafa M. M. EI-Meligy, Synthesis of Novel Benzofuran and Related Benzimidazole Derivative for Evaluation of In Vitro Anti-HIV-1, Anticancer and Antimicrobial Activites. Arch Pham Res., 2006; 29(10):826-833.
9.  Gurubasavaraja Swamy P. M. and Agasimundin Y.S., Synthesis and Antimicrobial Activity.of same Novel Chalcones Containing 3-Hydroxy Benzofuran. Acta Pharm. Sciencia, 2008; 50:197-202.
10.  Goudarshivannanavar B C, Jayadevappa H, & Mahadevan K M, A convenient synthesis of 2(2-benzo[b]furo)indoles and benzofuropyrazoles. Indian Journal of Chemistry, 2009; 48B:1419-1423.
11.  Murat Koca, Suleyman Servi, Cumhur Kirilmis, Misir Ahmedzade, Cavit Kazaz, Berna Ozbek, Gulten Otuk, Synthesis and antimicrobial activity of some novel derivatives of benzofuran: part 1. Synthesis and antimicrobial activity of (benzofuran-2-yl) (3-phenyl-3-methylcyclobutyl) ketoxime derivatives. Eur. J. Med. Chem., 2005; 40:1351-1358.
12.  Paula Veronica Podea, Monica Ioana Tosa, Csaba Paizs and Florin Dan Irimie, Chemoenzymatic preparation of enantiopure L-benzofuranyl- and L-benzo[b] thiophenyl alanines. Tetrahedron: Asymmetry, 2008; 19:500-511.
13.  Basawaraj Raga, Goled S.N., Parmeshwarappa G. and Sangapure S.S., Synthesis and biological activity of some pyridyl substituted benzofurans. Indian Journal of Heterocyclic chemistry, 2009; 18:325-328.
14.  Basawaraj Raga, Shashikanth Goled, Hugar M.H. and Sangapure S.S., Synthesis and biological evaluation of benzofuro[3,2-d] Pyrimidines. Indian journal of heterocyclic chemistry, 2009; 18:329-332.
15.  Shazia N. Aslam, Philip C. Stevenson, Sara J. Phythian, Nigel C. Veitch and David R. Hall, Synthesis of cicerfuran, an antifungal benzofuran, and some related analogues. Tetrahedron, 2006; 62:4214-4226.
16.  Hatem A. Abdel-Aziz, Amal A.I. Mekawey, Stereoselecive synthesis and antimicrobial activity of benzofuran-based (1E)-1-(Piperidin-1-yl)-N2-arylamidrazones. Eur. J. Med. Chem., 2009; 44:4985-4997.
17.  Wahab M Khan, Jahangir M. Alam, Rashid M. A. and Chowdhury R., A new structural alternative in benzo[b]furans for antimicrobial activity. Bioorg. Med. Chem., 2005; 13:4796-4805.
18.  Li, W.D., Lee E.B., Kang S.S., Hym J.E., Whang W.K., Activity-guided isolation of saponins from Kalopanax pictus with anti-inflammatory activity. Chem. Pharm. Bull, 2002; 50:900-903.
9. / SIGNATURE OF CANDIDATE / (abhishek raj pachori)
10. / REMARKS OF THE GUIDE
11. / NAME AND DESIGNATION OF11.1 GUIDE / DR. SADATH ALI
M.Pharm Ph.D
11.2 SIGNATURE
11.3 CO-GUIDE (IF ANY) / Mr. SYED SHAKEEL AHMED
M.Pharm
LECTURER
11.4 SIGNATURE
11.5 HEAD OF DEPARTMENT
11.6 SIGNATURE / Mr. SUDHEENDRA
M.Pharm (Ph.D)
PROFESSOR
12. / REMARKS OF THE CHAIRMAN AND PRINCIPAL12.1 SIGNATURE
PROF. SYED SANAULLAH
M.Pharm (Ph.D)
(Principal)