Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 78 Review Paper Diverse Pharmacological aspects of Benzimidazole Derivatives: A ReviewSreenivasulu Enumula, Anees Pangal, Muiz Gazge, Javed A. Shaikh and Khursheed Ahmed* Dept. of Chemistry & Post Graduate Research Centre, Abeda Inamdar Sr. College of Arts, Science & Commerce, Camp, Pune – 411001, INDIA Available online at: www.isca.in, www.isca.me Received 6th February 2014, revised 1st March 2014, accepted 15th March 2014Abstract Benzimidazole is the heterocyclic compound formed by the fusion of benzene and imidazole ring. Benzimidazole analogs are of great significant because of their various clinical applications and biological activity. Benzimidazoles are considered as an optimistic class of bioactive heterocyclic compounds that possesses a range of biological activities. The work in this article relates to benzimidazole as it is a versatile heterocycle possessing a wide spectrum of biological activities like antimicrobial, antiviral, antidiabetic, anticancer activity, numerous antioxidant, antiparasitic, antihelmintics, antiproliferative, antiHIV, anticonvulsant, anti-inflammatory, antihypertensive, antineoplastic, proton pump inhibitor and antitrichinellosis. Benzimidazoles possess significant biological activities likepotential antitumor agents, smooth muscle cell proliferation inhibitors and in various areas of chemistry. Keywords: Diverse, pharmacological, benzimidazole, heterocyclic, fusion, imidazole ring. IntroductionBenzimidazole is a well known famous structure in medicinal chemistry with various biological activities. It is a benzannulated ring system in which benzene ring is fused with a five member ring system having hetero atom at 1 and 3 positions. The properties of benzimidazole and its analogs have been studied since over hundred years. However a special interest of researchers towards benzimidazole derivatives was originated by the fact that 5, 6-dimethyl-1-(-Dribofuranosyl) benzimidazole is an basic part of the structure of vitamine B12. Moreover benzimidazole is a structural unit of naturally occurring nucleotide, due to which it easily interacts with the biopolymers of living system. This character is responsible for its numerous biological aspects like antihelminthic, antifungal, anti-allergic, antimicrobial4-6, antiviral and antineoplasticactivities. Since proteases have been linked with several disease states, including thrombosis, inflammation, bronchoconstiction and tumor growth and invasion. The incorporation of the nucleus is an important synthetic strategy in studies of antimicrobial drug discovery. In the past few decades, benzimidazole and its derivatives have grasped much attention due to their chemotherapeutic values10. Furthermore, the pharmacological properties as well as therapeutic applications of benzimidazole depend upon the pattern of substitution and recently they are reported to possess many pharmacological activities. This review highlights the importance of Benzimidazole in medicinal world along with a few examples of clinically used drugs. Additionally review of some of the work concerning benzimidazole reported in the recent literature has also been provided. Antibacterial Activity He et al. reported synthesis of a series of benzimidazole with general molecular structure (1) which exhibits potent broad spectrum antibacterial activity and started a research program to discover novel antibiotics against Gram positive bacteria by targeting rRNA11. NN NH NAr Cl Cl Figure-1 General structure for benzimidazole derivatives (1)Kumar et al. synthesized some novel 2-(6-fluorochroman-2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazoles and found that they exhibited good antibacterial activity against Salmonella typhimurium. They also reported synthesis of a series of functionalized novel benzimidazole derivatives and evaluated for their potential antibacterial12. Synthesis of benzimidazole as 1-(substituted-methyl)-2-(substituted-phenyl) benzimidazole (2) was reported by Leonardo et al. Compounds 2a, 2b and 2c were screened for their antibacterial activity against S. aureus, B. pumillus and P. Aeurugenosa. Compound 3a showed MIC (6.25) at 100M/mL and exhibited good antibacterial activity13. Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 79 Synthesis of 2,3,4,-trisubstituted-1,2-dihydropyrimido[1,2-]benzimidazole derivatives (3) were reported by Deshmukh et al. The compounds were tested for their fungicidal activities against Aspergillus niger MTCC-2255 and Penicillium chrysogenum-NCIM-723 using Greiseofulvin as control14. The efficient synthesis of novel 3-chloro-1-5-(2-methyl-1bezimidazol-2-yl)-4-(substituted) phenylazetidin-2-one (4) was reported by Ansari et al. Compounds were screened for antibacterial activity against B. substilis and E. coli and compound 4a, 4b and 4c shown MIC at 100g/mL, 100g/mL and 200g/mL doses15. The two series of benzimidazole derivatives were synthesized by Kazimierczuk et al., the first one was based on 2-thioalkyland thioaryl substituted benzimidazole (5), the second one was based on 5,6-dinitrobenzimidazole (6) and the antibacterial activity of the compound against Stenotrophomonas malthophilia was examined16. Ansari and Lal evaluated novel azetidine-2-one for antibacterial and antifungal activity against B. subtilis, E.coli, C. albicans, A. niger and A. flavus. All these tested compounds were less effective against Gram negative bacteria17-18. Some benzimidazole 2-substituted-1-[{(5-substituted-alkyl/aryl)-1,3,4-oxadziazolyl-2-yl}] derivatives were assessed for antimicrobial activities against Gram +ve and Gram –ve bacteria by Ansari and Lal and they are moderately active against tested organism17-18. Gupta and co-workers prepared 2-thiohalogenonitrophenyl benzimidazole (7) and screened them for their antifungal activity against H. sativum, A. niger and F. oxysporum. The percentage inhibition of the fungal spores was recorded at 10ppm19. Ghoneim et al. prepared 2-[(4-aminophenyl)sulphonyl] derivative (8) of benzimidazole and tested the antimicrobial activity of compounds against E. coli using agar diffusion method. All 4-amino and 2,4-diaminophenylsulphonyl derivatives showed antimicrobial activity20. NN R1 NR R = piperizine, dimethylamine, diethylamine = Cl NN N H2N CN R R = -OCH, -OH NN NNS N Cl Ar O Ar = 2-PhCl, 2-PhOHFigure-2 General Structures for benzimidazole derivatives (2), (3) and (4) NN = R, R = CHCHN(CH, R = H, R = COOH =SR R3 R2 R1 H2C Cl Cl NN R = CHCHN(CHR = CHCHN(CR = O2N NO CH R Figure-3 2-thioalkyland thioaryl substituted benzimidazole (5) & 5, 6-dinitrobenzimidazole (6) NN R = 2,4-DNP, 2,6-DNT, 2,4,6-TNP, 2-chloro-4,6-DNP, 2-methyl-4,6-DNP, 2-chloro-4-bromo-3,5-DNPSR NN R = 4-NH, 2,4-diNH O O R Figure-4 2-mercaptobenzimidazole (7) & 2-[(4-aminophenyl)sulphonyl] derivative (8) Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 80 Various benzimidazoles were also prepared and evaluated by Mane et al. towards A. brassicicola, F. oxysporum , S.aureusand Escherichia. coli at 500 ppm concentration. The compounds with nitro and chloro substituent possess good antimicrobial activity against21. Mavrova and co-workers synthesized the 1H-benzimidazole-2-yl thioacetylpiperazine derivatives (9, 10, 11) and screened them for in-vitro activity in contrast to T. spiralis and in-vivo anti-nematode activity against S. obvelata. Most of the synthesized compounds exhibit higher activity towards T. spiralis than albendazole and comparable to that of ivermectin. Few compounds exhibited 96.0%, 98.2% and 100% activities at a dose of 200µg/ml after 48h. Some of the compounds were most active with 76%, 73% and 77% towards S. obvelata22. Yadav et al. synthesized a series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids and tested them for antifungal activity and found two compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimid-azol-2-yl] benzenesulfonic acid and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid were most effective23. Antiviral Activity A new series of 2-arylbenzimidazoles (12) was reported by Vitale et al. They assessed them for antiviral activity and antiproliferative. Compounds were screened against Flaviviridae family, i.e. Flaviviruses and Pestiviruses, Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdo-viridae and Reoviridae, Herpesviridae and Poxviridae. Compounds 12a, 12b and 12c showed moderate activity against Yellow Fever Virus24. A new series of benzimidazole and substituted benzimidazole -L- and -D-2’-deoxyribonucleosides derivatives was reported by Budow et al and screened for antiviral activity against selected RNA and DNA viruses25. Synthesis of 2-(benzylthio)-5, 6-dichloro-1-(ribofuranosyl)benzimidazoles (13) was reported by Devivar et al 10. Compounds 6a, 6b and 6c performed anti-viral activity towards HSV-1 and HCMV and compound 6c shown maximum activity at 90% inhibitory concentration (M)26. S N N O R S N N O R R1 R = H, CHR = H, CH, NO, Cl, R = CH, Cl S N N O R S O NH R = H, CHFigure-5 The 1H-benzimidazole-2-yl thioacetylpiperazine derivatives (9, 10, 11) NN NN Cl NH NN Cl NH Cl Figure-6 2-arylbenzimidazoles derivatives (12) Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 81 NN R O OH OH OH HO HO R = SCH, SOCH, SOPhFigure-7 2-(benzylthio)-5, 6-dichloro-1-(-D-ribofuranosyl)benzimidazoles (13) Some 7-(arylamidoalkyl)-3,4-diphenyl-isoquinolinyl-[1,5-c]-benzimidazoles (14) have been synthesized by Pandey and Shukla and were evaluated for their in vivo against influenza virus (IV) by inoculating it in 10 day old embryonated hen’s egg at the concentration of 0.5 mg per embryo. After 48 h it was found that the isoquinonyl benzimidazole derivative with nicotinamido group showed the maximum activity27,21Various benzimidazol-2-ylalkyl N-aryldithiocarbamates (15), 2-arlimino-4-methyl/H-2H, 4H[1,3,4]dithiazino[4,5-a]benzimidazole (37), 1-aryl-4-methyl/H-1, 2-dihydro-4H-[1,3,4]thiadiazino[4,5-a]benzimidazole-2-thiones (38) 1-aryl-4-methyl/H-1, 2-dihydro-4H-[1,3,4]thiadiazino[4,5-a]benzimidazole-2-ones (39) were synthesized and tested for their antiviral activity by Yadav and Pal28. Kristina et al. prepared a set of 2-substituted-5-amidino-benzimidazole (16) derivatives bearing amidino substistuent at C-5 of benzimidazole ring by substituting various heterocyclic nuclei at C-2 and were evaluated for their antiviral activity towards coxsackie viruses and echo viruses. The most selective activity towards coxsackie viruses and echo viruses was observed with the compound having pyridine ring at C-229. Some new 10-(a-p-benzimidazolyl-1-aminobenzyl) phenothiazines (17) have been synthesized and their antiviral activity was performed against JEV and HSV-1 by Bishnoi et al30. Anti-Inflammatory Activity Synthesis and anti-inflammatory activity of phenyl benzimidazole (18) was reported by Leonardo et al. Compounds 1a, 1b, 1c and 1d were screened for anti-inflammatory activity and they showed percent inhibition (22.1%, 52.2%, 54.6% and 49.6%) at 50 mg/kg each doses. By these values the compound 1c showed maximum (54.6%) inhibition of edema at doses of 50mg/kg31. Ph Ph R1 R R = H, R = salicylamido NH S R CSNHR NH R1 R1 = Heterocyclic substituent = Amidino substituent N HN N S R R = Substituted phenylFigure-8 Benzimidazole derivatives (14-17) NN R1 R = morphine, diphenylamine, dimethylamine, imidazole = Cl NR Figure-9 Phenyl benzimidazole derivatives (18) Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 82 Khan and Nandan synthesized some 2-substituted benzimidazoles and assessed them for analgesic and anti-inflammatory activities. The compounds exhibited good anti-inflammatory activity at 50mg/kg dose32. Evans et al reported a new synthesis 1H-benzimidazole and screened their anti-inflammatory activity by assessing on rat and indomethacin is used as standard. The result shwed 30% or greater reduction in non-injected paw volume against the result for indomethacin compared when compared to control33. Antioxidant Activity Synthesis of some 6-flouro-5-substituted benzimidazole (19)reported by Alagoz et al. and tested for antioxidant activity and compound (19e) showed strong anti-oxidant effect on superoxide anion at 0.001M concentration34. NN R = 4-CH10, 4-CH10N, 4-C4-C, 4-C, R = H, Br, OCH F NH R1 Figure-10 6-flouro-5-substituted benzimidazole derivatives (19) Antiulcerative Activity Pantoptazole, Omeprazole, lansoprazole, Rabeprazole are some commercially available benzimidazole-based drugs. These drugs are used in combination with antibiotics to treat the gastric infection with H. pylori and reduce the gastric acid output by inhibiting the H+/K+-ATPase proton pumps35. Although H2 antagonist are also prescribed but proton pump inhibitors (PPIs) show faster pain relief, more rapid ulcer healing and far greater efficacy in oesophageal reflux diseases. PPIs are weak bases which are absorbed from the small intestine and delivered to the parietal cell via blood where they accumulate in the acidic, tubulovesicular system. In actively secreting parietal cells where tubulovesicular space is very highly acidic, they converted to a cyclic sulfonamide. These reactive sulfhydryl reagents binds to the active site of the enzyme by covalent interaction with the thiol groups of cysteine residue located at position of 813 and 822 between transmembrane domain 5 and 6 of the alpha subunit of the /K-ATPase. The interaction of rearranged inhibitory sulfonamides derived from PPIs with the active site of the enzyme prevents proton pumping and production of hydrochloric acid. Hence helps in treating ulcers36-40. Series of novel pyrimidyl-thio-methyl- benzimidazole 20(a) pyrimidyl-sulfinylmethylbenzimidazole 20(b) synthesized and reported by Bariwal et al. Compounds evaluated for the antiulcer activity. Compound 20a and 20b at 10 and 30 mg/kg doses reduced the ulcer formation significantly comparable to standard (Omeprazole) and 20b (sulfinyl derivative) compound was more effective than 20a (thio derivative)41. S NH NN S NH O Figure-11 Novel pyrimidyl-thio-methyl-benzimidazole 20(a) andpyrimidyl-sulfinylmethylbenzimidazole 20(b) Antileishmanial Activity Solominova et al synthesized 2-benzimidazole carbamic acid methyl ester derivatives (21). Compounds 20a and 20b shown anthelmintic activity against Nippostrongilus, Ankilostoma and Haemonhus larvae that exceeded 65% upon per oral administration in animals (rats, sheep, dogs) at a dose of 2.5-50mg/kg. In another group of animal inhibition action is below 40% upon per oral administration in a dose of 50-100mg/kg42. S NN NHCOOCH R1 = COOCHCHOCH, CONHCHCHCOOCHFigure-12 2-benzimidazole carbamic acid methyl ester derivatives (21) Mavrova et al. synthesized 5(6)-(un)substituted-1H-benzimidazol-2-yl thioacetyl piperazine derivatives and assessed for anthelmintic activity against T. spirilis. Compound 2-(2-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-5(6)-methyl-1H-benzimidazole (22) was the most active43. NH S N O N Cl Figure-13 2-(2-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-5(6)-methyl-1H-benzimidazole (22) Vallezo et al. successfully studied COMFA on 1H-benzimidazole derivatives and determine the tautomeric form which fits a target receptor in E. histolytica. The results showed Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 83 that the anti-amoebic activity is favored with electron deficient group at 2nd position and steric size at position 5 of benzimidazole ring44. Pentamidine, an aromatic diamidine is a well known drug used to treat leishmaniasis45. Despite its efficiency, it is non-functional by problems including poor bioavailability and other unpleasant side effects46. So as to overcome these limitations many structural modifications have been done and which deal with linking both benzamidine groups. The resultant compounds like Furamidine (23)47 and 4-4’-piperazine-1,4-diyl)bisbenzamidine (24)48 were recently come out as encouraging drug molecules for the treatment of Trypanosomiasis and P. carinii pneumonia, respectively. Mayence et. al. masked the amidine groups by encapsulating into unsaturated cyclic system specially benzimidazole system49. The resultant compounds were much more active against Leishmania donovanii .Torres et al. had also made some hybrid compounds by using benzimidazole and pentamidine with central pentyldioxyphenyl piece at the end and the terminal amidine groups were substituted by 5-substituted benzimidazole frame50. The results obtained were much in agreement because many of the compounds exhibited activity in comparable withstandard drugs meteronidazole and pentamidine. Only compound with -CF at 5th position ring exhibited moderate anti-malarial activity with IC50 of 6.53µM. Marrova et al. synthesized some new piperazine derivatives of (1-benzimidazol-2-ylthio)acetic acid (25-28) and investigated them for antihelmintic efficacy in order to compare them with albendazole and ivermectin. The same group of scientist have also synthesized 2-substituted-[1,3]thiazolo[3,2-a]benzimidazol-3(2)-ones. SAR of these compounds was also comparable to the known drugs, albendazole and ivermectin. These results proved the hypothesis of introduction of a condensed ring in the benzimidazole system, favored to the interaction of these compounds with the biological targets51. O O H2N NH HN NH n H2N HN O NH NH NH NH N N H2N HN Figure-14 Furamidine (23) & 4-4’-piperazine-1,4-diyl)bisbenzamidine (24) O O H2N NH HN NH 3 O O 3N NN R1 R1 R2 R2 = H, OCH, CH, NO, CF = H, OCHFigure-15 5-Substituted Benzimidazole Derivatives Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 84 Anticancer Activity Cancer characterized by rapid or slow uncontrolled growth of cells.On the basis of the type, a number of anticancer drugs are now a days in medicinal practice. Carbomethoxy-substituted benzimidazole derivatives of UK-1 [a bis (benzoxazole) natural product] were obtained from Streptomyces strains by Kumar et al. and assessed its cytotoxicity gainst four cell lines such as PC-3, HT-29, MCF-7 and HL-60. Only one compound methyl-2-[2-(2-hydroxyphenyl)-1,3-benzooxazol-4-yl]-1H-benzimidazole-4-carboxylate (29) possesses activity towards the tested cell lines aginst a concentration ranging from 7.0 to 100µM52. Vedula and co-workers screened new styryl sulfones for anticancer activity against different cell lines. Out of the various molecules prepared only one compound 6-chloro-1H-(benzo[d]imidazol-2-yl) methyl[(E)-2-(4-chloro-3-methylphenyl)-1-ethenyl] sulphone (30) showed 51% inhibition of tumour growth in mice with HT-29 at 400mg/kg orally53. Ramla et al. derivatised 2-(1-benzyl-2-methyl-1H-benzimidazol-5-ylimino)-3-(substituted)-thiazolidines-4-ones and 3-(2-methyl-1H-benzimidazol-5-yl)-2-substitutedthiazolidines-4-ones. They significantly assessed them for antitumor activity against the EBV-EA activation by introducing 12-O-tetradecanoyl phorbol-13-acetate. 3-benzoyl-2-(1-benzyl-2-methyl-1H-benzimidazol-5-yl-imino)thiazolidin-4-one (31).54. Hranjec et al prepared a novel series of substituted benzimidazole Schiff bases. The prepared hydrazones were screened for antiproliferative activity in-vitro and showed antiproliferative activity on the tested cell lines at higher concentrations55. Benzimidazole-4,7-diones substituted at position-2 were designed by Gellis et al. Their anti-cancer activity was studied on lung cancer, colon cancer and breast cancer cell lines. Out of thess, 2,20-bis(chloromethyl)-1,10-dimethyl-5,50-bi(1H-benzimidazole)-4,40,7,70-tetraone (32) possessessignificant cytotoxicity against mitomycin C56. NH S N O N NH S N O N NH S N O N Cl NH S N O N Cl Figure-16 Piperazine Derivatives Of (1H-Benzimidazol-2-Ylthio) Acetic Acid (25-28) NN N NS O O O- O NH ON HO NH Cl Cl S O O Figure-17 29 = methyl 2-[2-(2-hydroxyphenyl)-1,3-benzooxazol-4-yl]-1H-benzimidazole-4-carboxylate, 30= 6-chloro-1H-(benzo[d]imidazol-2-yl) methyl[(E)-2-(4-chloro-3-methylphenyl)-1-ethenyl] sulphone, 31= 3-benzoyl-2-(1-benzyl-2-methyl-1H-benzimidazol-5-yl-imino)thiazolidin-4-one Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 85 Various heterocyclic benzimidazole derivatives (33-36) were preparedfrom succinic acid, homophthalic acid and 2,3-pyrazinedicarboxlic acid and various substituted diamines by Sondhi et al. All these compounds screened for their antitumor assay at 50mg/kg showed good anticancer activity against IGROV-1, MCF-7 and SF-295 human cancer cell lines57. 1-methylene-2, 3-diaryl-1, 2-dihydropyrazino [1,2-a] benzimidazoles (37) and some 1-(2-arylvinyl)-3-arylpyrazino[1,2-a]benzimidazole derivatives (38) have been synthesized and their anticancer activity was reported by Demirayak et al. log10GI50 values are less than –4 gainst standard drug58. The synthesis of series some of benzimidazole like: 2-[(4-oxothiazolidin-2-ylidene)-methyl (39) and (4-amino-2-thioxothiazol-5-yl) benzimidazoles (40), 2-[(4-fluorobenzylidene (41) and cycloalkylidene)-cyanomethyl] benzimidazoles was carried out by Refaat et al. All the prepared compound were assessed against three cell line , HEPG2 and MCF759. N NN Cl Cl O O O O Figure-18 2,20-bis(chloromethyl)-1,10-dimethyl-5,50-bi(1H-benzimidazole)-4,40,7,70-tetraone (32) N O N O N O N O Figure-19 Various heterocyclic benzimidazole derivatives (33-36) NN N R1 R2 NN N R1 Ar = H, CH, OCH, CI = H, CH, OCH, CI, NOAr = Cl Cl Cl O S Figure-20 37 = 1-methylene-2,3-diaryl-1,2-dihydropyrazino[1,2-a]benzimidazoles, 38 = 1-(2-arylvinyl)-3-arylpyrazino[1,2-a]benzimidazole derivatives Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(4), 78-88, April (2014) Res. J. Chem. Sci. International Science Congress Association 86 NN HO NH O O NN HO NR O S NN CN F R R = Ph, CHPhR = Cl, COOHFigure-21 Benzimidazole Deriviatives (39-41) Anti-Diabetic Activity A synthesis of a series of novel and substituted benzimidazole derivatives (42) was reported by Kumar et al. Compounds shown anti-diabetic activity against DPP-IV and PTP-IB. 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