SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF BENZIMIDAZOLE DERIVATIVES
M.Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560041
By
Mr. PATEL SANKETKUMAR M B.Pharm
Under the Guidance of
Mr. GILES D M.Pharm
Asst. Professor
Department of Pharmaceutical Chemistry,
Acharya & B.M. Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara Post,
Bangalore -560090.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 /Name of the candidate and address
/Mr. Patel Sanketkumar M
59, Girivar Homes, Opp. Madhav School,Vastral Ring Road, Ahmedabad,
Gujarat.
2 / Name of the institution / ACHARYA & B.M. REDDY COLLEGE OF PHARMACY,
89/90, Soldevanahalli, Chikkabanavara post, Hesaraghatta main road,
Bangalore - 560090
3 / Course of study and subject /
MASTER OF PHARMACY
(PHARMACEUTICAL CHEMISTRY)4 / Date of the admission / 6th June 2009
5 /
Title of the topic:
SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF BENZIMIDAZOLE DERIVATIVES6.0
7.0 /
Brief resume of the intended work
6.1 Need for study:Non steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used drug category against inflammation, mild to moderate pain and fever. Specific uses also include the treatment of headaches, arthritis, sports injuries, and menstrual cramps. Their use is mainly restricted by their well known and serious adverse gastrointestinal side effects such as gastro duodenal erosions and ulcerations.
Benzimidazoles are bicyclic aromatic organic compounds consisting of the fusion of benzene and imidazole. It is one of the most promising heteroaryl moiety that yielded many successful drugs like omeprazole and mebendazole. Benzimidazole moiety fulfills the minimum structural requirements that are common for anti-inflammatory. In the past, benzimidazole derivatives showed potential anti-inflammatory and analgesic activity in animal models of inflammation and pain.
Several biological applications like anti-microbial,1-25 antiviral,26-28 antiprotozoal,29-31 anti-inflammatory,32-34 anthelmintic,35 anti-hypertensive,36,37 anti-tumor,38,39 activities have been reported for benzimidazole derivatives.
The following are some of the benzimidazole derivatives found to possess the above mentioned activities:
1. 2,5- and/or 6-substituted benzimidazole derivatives.4
2. 2-(2-benzylthiopyrimidin-4-yl)substituted benzimidazoles.7
3. Thiazine substituted benzimidazoles.9
4. Chiral substituted benzimidazole derivatives.11
5. Benzimidazole carbamate derivatives.14
6. Piperidine substituted benzimidazoles.25
7. Nitro- & halogen substituted benzimidazole derivatives.29
8. Substituted carboxamido benzimidazole derivatives.37
9. Pyrazino[1,2-a] benzimidazole derivatives.44
The following are important benzimidazole drugs which are available in the market:
Thus in this study, a strategy has been planned to synthesize newer benzimidazole derivatives and subsequently study for their biological activities.
The aim is to have a drug with better efficacy, less toxicity and fewer side effects. Therefore the synthesis of benzimidazole system has been undertaken for investigation of biological activity.
6.2 Review of literature:
Ø Rajanarendar E et al synthesized a series of novel 2/3(1H-benzimidazol-2-yl)-N-(5-methyl-3-isoxazolyl)-benzamides, acrylamides and propionamides. He evaluated antimicrobial activity of the synthesized compounds and found that substitution on phenyl ring decreases activity.1
Ø Baviskar BA et al synthesized novel benzimidazolyl chalcones and screened for in vitro anti microbial activity by cup plate method. The presence of α, β- unsaturated keto group in chalcones was found to be responsible for their biological activity.2
Ø Umare VD et al synthesized 2-substituted-6-nitro-N-1-β-D-glucopyranosyl benzimidazoles in high yields by condensation of 2,3,4,6-tetra-O-acetyl-α-D-glucopyrasnosyl bromide with 2-substituted 6-nitro-1H-benzimidazoles and evaluated for their antibacterial activities.3
Ø Oren I et al synthesized a series of novel 2,5- and/or 6-substituted benzoxazole and benzimidazole derivatives and screened for their in vitro antimicrobial activity against gram-positive, gram-negative microorganism and yeast. Among all synthesized compounds 5-chloro-2-(2-cyclohexylethyl) benzimidazole was found to be most active compound against the screened gram positive bacteria.
Benzimidazole ring holds 2-cyclohexylethyl moiety on position 2 together with chlorine atom at fifth position increase the activity.4
Ø Ansari KF et al synthesized benzimidazole derivatives and screened for their in vitro antimicrobial activity. Number of carbon atom increases in side chain at 2-position of oxadiazole heterocyclic ring and para-substitution on benzene nucleus increase the activity.5
Ø SB Jadhav et al synthesized two series of benzimidazole derivatives by the condensation of different 2-substituted benzimidazoles with 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (CMIC) and 3-(2,4-di chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (DCMIC) and evaluated for their antibacterial and antifungal activity. All the compounds exhibited significant to moderate antibacterial and antifungal activities.6
R= H, CH3, C2H5, n-C3H7, -CH2-Ph
2a-e (X=H) and 3a-e (X=Cl)
Ø Goudgaon NM et al synthesized 2-(2-benzylthiopyrimidin-4-yl) substituted benzimidazoles and evaluated for their antimicrobial activity.
Among them few derivatives showed good antibacterial and antifungal activity.7
Ø Singh DN et al synthesized novel benzimidazole incorporated anthraquinones and evaluated for their antifungal activity.
The presence of para chloro benzene showed significant antifungal activity.8
Ø Sundari V et al synthesized 3,5-diaryl-4-(2-ethoxybenzimidazol-2-yl)-tetrahydro-1,4-thiazine-1,1-dioxides and 2,6-dimethoxycarbonyl-3,5-diaryl-4-(2-ethoxybenzimidazol-2-yl)-tetrahydro-1,4-thiazine-1,1-dioxides and evaluated for their antibacterial, antifungal, acute toxicity & antihistaminic activity.
Compound 3 and 6 showed good activity due to presence of –Cl substituents.9
Ø Jadhav GR et al synthesized 4-{[4,6-difluoro-1-substituted-1H-benzo[d] imidazol-2-yl] methoxy} benzonitriles by alkylation with alkyl & aryl halides and evaluated for their in vitro antibacterial activity. All the compounds showed moderate activity.10
Ø Shelar AR et al synthesized new chiral substituted benzimidazoles evaluated for their antimicrobial activity. All the compounds showed promising antibacterial activity.11
Ø Parmar S et al 1-methyl[(N-alkyl phthalyl)-benzimidazolo]-3'-chloro-4'-substituted azetidin-2-ones and evaluated for their antimicrobial activity. Some of the compounds showed promising antibacterial activity due to the presence of nitro group on the phenyl.12
R= H, CH3
Ø Goker H et al synthesized a series of novels N-(alkyl)-2-phenyl-1H-benzimidazole-5-carboxamidines evaluated for their in vitro antibacterial activity. [1-(2,4-dichorobenzyl)-N-(2-diethylaminoethyl)-1H-benzimidazole-5-carboxamidine] having 3,4-dicholorophenyl group at C-2 position showed greatest activity.13
Ø Canan KUS et al synthesized benzimidazole carbamate derivatives and evaluated for their in vitro antifungal activity by agar diffusion method.
Compound / R
1 / Cl
2 / 4-morpholinyl
3 / 1-pyrrolidinyl
4 / 3-methylpiperidin-1-yl
5 / (pyridine-3-ylmethyl)-amino
Compound 5 exhibited slight activity. However, when their activity was compared with standards, none of the novel benzimidazole carbamate derivatives exhibited significant activity.14
Ø Goker H et al synthesized 1,2,5(6)-trisubstited benzimidazoles and evaluated in vitro for antimicrobial activity. Presence of chloro group at C-5(6) and methylpiperidine group at C-2 of benzimidazole increase the activity.15
Ø Vijiyaraghavan S et al synthesized series of mannich bases by microwave irradiation technique and evaluated for their antimicrobial activity.
comp / R1 / R2
5a / H / 4-Fluorophenyl
5b / H / 3-Chlorophenyl
5c / H / 4-Nitrophenyl
5d / H / 4-Hydroxyphenyl
5e / H / 2,6-Dichlorophenyl
5f / H / 2-Chloro-4-flurophenyl
5g / H / 3-Methylphenyl
5h / Morpholinyl
Compound 5a and 5d exhibited moderate activity at high concentration, 5f showed excellent activity against all bacteria at high concentration , 5b, 5e,and 5g displayed average activity and 5h proved to be inactive.16
Ø Gulgun AK et al synthesized some benzimidazoles derivatives. The presence of nitro and amino group was responsible for their in vitro antifungal activities by tube dilution technique.17
Ø El-masry AH et al synthesized oxadiazole by reaction of 3-(2-methylbenzimidazol-1-yl)propanoic acid hydrazide with CS2/KOH. Presence of oxadiazole compound found to be highly active was responsible for their antimicrobial activity.18
Ø Goker H et al synthesized new benzimidazolecarboxamides and evaluated for in vitro antimicrobial activity. Presence of 4-halogenated benzyl substituent at position 1 showed good antimicrobial activity.19
Ø Smith AA et al synthesized benzimidazole derivative from ibuprofen with o-phenylene diamine and tested for their antibacterial and antifungal activity.20
Ø Khalafi NA et al synthesized QSAR studies of benzimidazole and imidazole chloroaryloxyalkyl derivatives and evaluated for their antibacterial activity.21
Ø Kamlesh VP et al synthesized chelating properties of benzimidazole-salicylic acid combined molecule and tested for antifungal activity.22
Ø Zhang D et al synthesized series of novel actiononin derivatives containing a benzimidazole heterocycle linked as amide isostere. Compound with unsubstituted benzimidazole ring shows good in vitro antibacterial activity using broth microdilution method.23
Ø Goker H et al synthesized novel series of flavones and methyl-4H-1-benzopyran-4-ones carrying mono or diamidinobenzimidazoles and evaluated for antibacterial and antifungal activity. Compound having N-alkyl substituted amidinobenzimidazole at position C-6 of 2-phenyl-4H-1-benzopyran-4-one exhibited high antibacterial activitie.24
R= H, i-pr, n-butyl, cyclohexyl, benzyl
Ø Sundari V et al synthesized 2,6-diphenyl-3-methyl-4-[2-benzimidazole-2-yl]-ethoxyimino] piperidines. Presence of OCH3 substituent group showed moderate biological activities.25
Ø Cheng J et al synthesized novel benzimidazole derivatives and 2-pyridyl-1H-benzimidazole-4-(N-R2-carboxamide) derivatives. With regards to R2 moiety, the presence of phenyl group showed potent selective activity towards antivirus.26
Ø Tewari AK et al synthesized N-substituted-2-substituted-benzimidazole derivatives, viz. 1-benzyl-2-substituted benzimidazole and 1-(p-chlorophenyl)-2-substituted benzimidazole. Presence of benzyl and p-chlorophenyl substituent’s were responsible for their antiviral activity.27
Ø Pandey VK et al synthesized 1,2-disubstituted benzimidazoles. He explained that presence of hydroxy substituted phenyl group was responsible for antiviral activity. Benzimidazole derivatives were effective against RNA-viruses inhibiting the formation of virus-induced RNA-polymerase, thereby preventing the DNA synthesis.28
Ø Kazimierczuk Z et al synthesized nitro- and halogen substituted benzimidazole derivatives and evaluated for antibacterial and antiprotozoal activity. 4,6-dichloro-2-(4-nitrobenzylthio)-benzimidazole showed the most distinct antiprotozoal activity.29
Ø Navarrete-Vázquez G et al synthesized a series of 2-(trifluoromethyl)-1H-benzimidazole derivatives. The isosteric substituents of hydrogen atom by chlorine, fluorine, trifluromethyl group and cyano group were evaluated for their antiprotozoal activity.30
Ø Torres-Gomez H et al synthesized series of ten hybrids from benzimidazole and pentamidine and tested in vitro against ptrotozoa. Some analogues showed high bioactivity in the low micromolar range, which make them more potent. Presence of methoxy group at position 5 of benzimidazole was more active.31
Ø Prasad AT et al synthesized some benzimidazole-2-carboxylic acid derivatives, and evaluated for acute anti-inflammatory activity against carrageenan induced rat paw edema model. Presence of carboxylic acid at position 2 was responsible for better anti-inflammatory activity.32
Ø Katarzyna K et al synthesized Chloro, bromo and methyl analogues of 1H-benzimidazole, 1H-benzotriazole and their N-alkylderivatives and screened for in vitro antiprotozoal activity.33
Ø Sham M. Sondhi et al synthesized a series of N-(acridin-9-yl)-4-(benzo[d]imidazol/oxazol-2-yl)benzamides by the condensation of 9-amino acridine derivatives with benzimidazole or benzoxazole derivatives. The presence of bis nature showed good anti-inflammatory activity and presence of chloro group substituent showed good analgesic activity.34
Ø Manjunath SY et al synthesized triheterocycles: [5'-(5"-substituted-3"-phenyl indol-2"-yl)-1',3',4'-oxadiazol-2'-yl-thiomethyl]benzimidazoles. Presence of Cl, OCH3, Br and CH3substituents were responsible for their anthelmintic activity.35
Ø Jat RK et al synthesized 5-substituted (amino)-2-phenyl-1-(2'-carboxy biphenyl-4-yl) benzimidazole and evaluated for their antihypertensive activity. Presence of ethyl group at position-2 and NH2group at position 5 of benzimidazole give good activity. In biphenyl ring carboxylic group at ortho position is necessary for activity.36
R = Phenyl, Ethyl
Ø Shah DI et al synthesized series of 5-(alkyl and aryl)carboxamido benzimidazole derivatives. Presence of lower alkyl groups at 5-position of benzimidazole shows better in vitro angiotensin II- AT1 receptor antagonism and in vivo antihypertensive activities.37
Ø Suthakaran R et al synthesized 4'-aryl/alkyl-2"-D-aldosugar disubstituted bis-benzimidazoles and screened for in vivo antitumor activity. Most of them showed significant activity.38
Ø Ramla MM et al synthesized 1-substituted-2-methyl-5-nitrobenzimidazoles and screened for antitumor activity.
The presence of NO2 group substitution at position 5, free NH group of benzimidazole, thiadiazole ring at position 1 of benzimidazole through a methylene group and having 2-propanoyl group at position 2 increase the activity.39
Ø Yi-Sheng X et al synthesized 4-oxo-4H-quinolizine-3-carboxylic acid derivatives bearing sulfamido, carboxylamido, benzimidazole and benzothiazole substituents. Presence of diketoacid group was responsible for HIV integrase inhibitory activity.40
Ø Thimmegowda NR et al synthesized novel series of trisubstituted benzimidazole derivative and its precursors. Presence of strong electronegative groups fluorine at para position and nitro group at meta position was responsible for potent inhibition against MDA-MB-231 breast cancer cell proliferation.41
Ø Tomio I et al synthesized a series of 1-cycloalkyl-2-phenyl-1H-benzimidazole-5-carboxylic acid derivatives. Presence of hydroxyl group substituents showed inhibitory activity against HCV NS5B RNA-dependent RNA polymerase.42
Ø Ramnatham V et al synthesized novel N-substituted 2-(4-styrylphenyl)-1H-benzimidazole and N-substituted-3[4-(1H-benzimidazole-2-yl)-phenyl]-acrylic acid tert-butyl ester and evaluated for antibacterial, anti-asthmatic and anti-diabetic activities. Presence of alkyl group substituent was responsible for good antibacterial activity.43
R =Methyl, Ethyl, Propyl, Butyl R= Methyl, Ethyl, Propyl
Ø Demirayak S et al synthesized pyrazino[1,2-a]benzimidazole derivatives and evaluated for anticancer activity.44
Ø Sharma D et al synthesized a series of 2-(substituted phenyl)-1H-benzimidazole and [2-(substituted phenyl)-benzimidazol-1-yl]-pyridin-3-yl-methanone and tested for their antimicrobial activity. Presence of p-nitro and p-hydroxy benzene at position C-2 of benzimidazole shows good activity.45
Ø Pan W et al synthesised a novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas and screened for their heparanase inhibitory activity.46
Ø Mavrova AT et al Synthesised piperazine derivatives of 5(6)-substituted-(1H-benzimidazol-2-ylthio)acetic acid. Presence of piperazine ring and –CH3 substitution at position 5(6) showed higher antihelminthic activity.47
Ø Algul O et al synthesized twelve 2-substituted benzimidazole, benzothiazole and indole derivatives using on both microwave irradiation and conventional heating methods. Presence of aryl group at position 2 of benzimidazole ring showed good inhibition of Hyaluronidase.48
Ø Gellis A et al synthesized benzimidazole-4,7-diones via microwave-assisted reaction using 2-chloromethyl-1,5,6-trimethyl-1H-benzimidazole-4,7-dione and their cytotoxicity has been evaluated on colon, breast, and lung cancer cell lines. Presence of quinines bearing substituent’s methyl group at position 5 and 6 and chloromethyl or substituted sulfonyl group at position 2 shows higher activity.49
6.3 Objectives of the study:
1. To synthesize some newer derivatives of benzimidazole
2. To characterize the synthesized compounds by different analytical techniques such as IR, NMR and Mass spectral data.
3. To screen the synthesized compounds for their anti-inflammatory, antimicrobial and analgesic activities.
4. To publish the research work in peer reviewed journal.
Materials and methods:
7.1 Sources of data
Databases like Chemical abstracts, Biological abstracts, Medline, and Journal of Chemistry section B, Indian Journal of Heterocyclic Chemistry, European Journal of Medicinal Chemistry, Bioorganic and Medicinal Chemistry Letters, Acta crystallographica, Helinet of RUGHS etc.
7.2 Method of collection of Data: