VERSATILITY OF BENZIMIDAZOLE AND ITS DERIVATIVES; AN INSIGHT

VERSATILITY OF BENZIMIDAZOLE AND ITS DERIVATIVES; AN INSIGHT

A. Saxena, V. Hegde, S. Mutalikdesai and M. Maste ^*

Department of Pharmaceutical Chemistry, KLE College of Pharmacy, KLE Academy of Higher Education and Research, Belagavi - 590010, Karnataka, India.

ABSTRACT: Benzimidazole, a fused heterocyclic moiety containing benzene and imidazole, has gained considerable attention in the field of medicinal chemistry due to its wide array of pharmacological activities. Be it as a antifungal, anticancer agent, proton pump inhibitors, anthelmintic, anti-microbial, analgesic, it has become an intrinsic part of the pharmaceutical world. The presence of Nitrogen in its heterocyclic ring has made it a more biologically active pharmaceutical agent. The fact that benzimidazole residue is a constituent of vitamin B12 supports its potential use in therapeutics. Benzimidazole derivatives are the structural isosters of naturally occurring nucleotides such as purine, allow them to interact effectively with the biopolymers of the living system such as proteins, enzymes, and receptors. Benzimidazoles exhibit significant activity as a potential anti-tumour agent, smooth muscle cell proliferation inhibitors, a treatment for intestinal cystitis, and in a diverse area of medicinal chemistry. The synthesis of novel benzimidazole derivatives remains as the main focus of medicinal research. This current review covers the chemistry and significance of benzimidazole and its derivatives, also helps to develop the derivatives of benzimidazole in this antimicrobial-resistant era.

Benzimidazole derivatives, Fused heterocycle, Anti-cancer, Anti-fungal

INTRODUCTION: Benzimidazole resembles the structure of Purine. This was discovered by Woolley in 1944. This lead to the further development of the benzimidazole moiety ¹. Looking at the nature and importance of this moiety it was thought that it would be worthwhile to design and develop some new benzimidazole derivatives which consist of oxadiazole moiety and screen their biological activity. Over the few decades of active research, it has been proved that Benzimidazole, as an important pharmacophore can show a large range of antibiotic effects and also fight against a huge number of bacteria ².

Based on the biological activity of the drug, they are classified into the following types.

Antituberculotic Activity:

1. Gobis K et al., have discovered various novel benzimidazole analogues and evaluated them for tuberculostatic activity.

The bromo substituted analogues showed excellent activity against Mycobacterium tuberculosis and Mycobacterium bovis with MIC ranging from 0.751.5 μg/mL. Compound (5-bromo-2-(2-cyclo-hexylethyl)-1H-benzo[d]imidazole) (1) showed the highest potency.

2. Ramprasad J et al., have prepared a new series of imidazo (1, 3, 4) thiadiazole-benzimidazole derivatives. The synthesized compounds were screened for antitubercular activity. It had been found that most of the derivatives showed anti-tubercular activity with a MIC of 3.125mg/mL. 5-chloro- 2- (6-(4-methoxyphenyl)-2-p-tolylimidazo [2,1-b][1,3,4]thiadiazol-5-yl)-1Hbenzo[d]imidazole (2) was the most potent derivative.

3. Gong Y et al., have synthesized various benzimidazole based compounds and evaluated them in replicating and non-replicating M. tuberculosis (Mtb). The study revealed that many compounds exhibited antitubercular activity but N-(1- cyclobutyl- 2- methyl- 6-morpholin benzo[d] imidazol-5-yl)-5-nitrofuran-2-carboxamide and N-(1- isopentyl- 2-methyl-6morpholino- 1H-benzo[d] imidazol-5-yl)- 5-nitrofuran-2- carboxamide (3) were more active.

4. Kalalbandi V K A et al., have synthesized a series of phenylprop-2-enoyl-benzimidazole deri-vatives. The synthesized compounds were screened for anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and cytotoxic activity. Compound (E)-3-phenyl-1(2-(p-tolyl)-1H-benzo[d] imidazol-1-yl)prop-2-en-1-one (4) exhibited a promising antimycobacterial and cytotoxic activity.

5. Ranjith P K et al., reported a series of positional isomers of 5 and 6-bromo-1[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1Hbenzimidazoles (5) derivatives. They were evaluated for antibacterial, antifungal and antitubercular activity. Several compounds showed activity against Mycobacteruim tuberculosis H37Rv strain.

6. Camacho J et al., have prepared a series of benzimidazole-5-carbohydrazide derivatives. The synthesized compounds were investigated for their abilities to inhibit β-hematin formation, hemoglobin hydrolysis, and in-vivo for their antimalarial efficacy. Selected analogues were evaluated for their antitubercular activity against sensitive Mtb H37Rv and multi drug-resistant MDR-Mtb strains. Compound N’-benzoyl-2-(5-nitrofuran- 2- yl)- 3H- benzo[d]imidazole- 5carbo-hydrazide (6) showed better antitubercular activity compared to rifampin against MDRMtb strains.

7. Desai NC et al., have synthesized benzimidazole bearing 2-pyridone motifs and evaluated for their in-vitro antibacterial and antitubercular activity. All compounds were also examined for their cytotoxic study on VERO cell line. Compound 1-((1-(1H-benzo[d]imidazol- 2yl)ethylidene)amino)- 6- ((3-chlorobenzylidene)amino)- 4- (4-nitrophenyl)- 2-oxo-1,2dihydropyridine-3,5-dicarbonitrile (7) was proved to be the most potent antitubercular agent.

8. Jadhav GR. et al., have discovered a series of novel [1,2,4]-triazol-1-yl, clubbed fluorobenzimi-dazole derivatives. The compounds were screened for their in-vitro antibacterial and antitubercular activity against Mycobacterium tuberculosis H37Rv strain. It was observed that 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4,6-difluoro-1-(3-fluorobenzyl)-1Hbenzo[d]imidazole compound (8) showed promising anti-tubercular activity.

9. Yoon YK et al., discovered new benzimidazole aminoesters and evaluated their antimycobacterial activity. Compound ethyl 2-(4-(trifluoromethyl) phenyl)- 1- (2morpholinoethyl)- 1H- benzo[d] imidazole-5-carboxylate (9) was found to be the most active with IC₅₀ of 11.52 μM.

10. Patel RV et al., ¹⁰ have synthesized a series of benzimidazole based 1,3,4-oxadiazoles derivatives and assessed them for their antimicrobial & antitubercular activity. The Nbenzothiazoyl acetamides series showed broad-spectrum antimicrobial & antitubercular potential. Amongst them 2-(5-((1H-benzo(d)imidazole-1-yl)methyl-1, 3,4-oxadiazol-2-ylthio)(4-methoxyphenyl)acetamide (10) showed most potent activity with MIC value of 6.25μg/mL.

11. Park B et al., ¹¹ have discovered novel 2,5,6-trisubstituted benzimidazole derivatives bearing ether or thioether linkages. The synthesized derivatives were screened against Mtb-FtsZ protein for antitubercular activity. Amongst the tested compounds 5-Butoxycarbonylamino-2-cyclohexyl-6-(4-fluorophenoxy)-1H-benzo[d]imidazole (11) showed potent activity with MIC value of 0.63μg/mL.

12. Gobis K et al., ¹² have synthesized series of novel cyclohexylpropanoic acid-derived nitrogen-based heterocyclic compounds and evaluated them for tuberculostatic activity. The derivatives (12) bearing benzimidazole like system showed most potent tuberculostatic activity with the MIC value ranging from 1.5 to12.5 μg/mL.

13. Gill C et al., ¹³ have reported novel (1,2,3) triazole clubbed with fluorine benzimidazole derivatives. These derivatives were evaluated for antitubercular activity. 1-((1-(2,4difluorophenyl)-1H-1,2,3-triazol-5-yl)methyl)-2-(3-fluorophenyl)-1H-benzo[d]imidazole (13) showed MIC value of 0.32μM, which was found to be better than the standard rifampin.

Anticancer Agent:

14. Reddy T S et al., have synthesized a series of pyrazole containing benzimidazole hybrids. These hybrids were evaluated for their anti-proliferative activity against three human tumor cell lines- lung (A549), breast (MCF-7), and cervical (HeLa). Compound 5-fluoro-2-(3-(4fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole (14) showed potent growth inhibition with IC₅₀ values of 0.83-1.81µM.

15. Paul K et al., ¹⁵ have generated new hybrids by combining the structural features of quinazoline and benzimidazole. Evaluation of these molecules was carried out against various cancer cell lines. The methoxy substituted compound (15) exhibited remarkable anticancer activity towards colon and prostate cancer cell lines with GI₅₀ value of 0.34 & 0.31 µM respectively.

16. Singla P et al., have prepared a new series of triazine-benzimidazole hybrids. These hybrids were evaluated for their inhibitory activities over various tumor cell lines & mammalian dihydrofolate reductase. (3-benzyl-2-methyl-3H-benzimidazol-5-yl)- (4-chloro-6-morpholin-4yl- [1,3,5]triazin-2-yl)-amine (16) showed broad spectrum antitumor activity with GI₅₀ value of 9.79μM. It also displayed DHFR inhibition with an IC₅₀ value of 1.05 μM.

17. El-Nassan H B et al., developed a series of novel 1, 2, 3, 4 tetrahydro[1,2,4]triazino[4,5a] benzimidazoles bearing a variety of aryl and heteroaryl groups at position 1. The compounds were tested in-vitro on human breast adenocarcinoma cell line (MCF7). Some of the test compounds showed potent antitumor activity, especially 1-(2-chlorophenyl)-1, 2, 3, 4tetrahydro [1,2,4]triazino[4,5-a] benzimidazole (17) displayed the highest activity.

18. Wang Y et al., have prepared a series of 1-benzene acyl-2-(1-methylindol-3-yl)benzimidazole derivatives and investigated them as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. 1-(3, 4, 5-trimethoxy-benzene acyl)-2-(5-methoxy-1-methylindol-3-yl)-benzimidazole (18) showed potent inhibitory and antiproliferative activity.

19. Shi L et al., designed a series of quinazoline and benzimidazole bearing fragments and identified them as dual c-Met and VEGFR-2 inhibitors. Among them N-(2-(4-fluorophenyl)1H-benzo[d]imidazol-6-yl)quinazolin-4-amine (19) exhibited the most potent inhibitory activity against c-Met and VEGFR-2 with IC₅₀ of 0.05µM and 0.02 µM respectively. It also showed the highest anticancer activity against the cancer cell lines with IC₅₀ of 1.5µM against MCF-7 and 8.7µM against Hep-G2.

20. Wang W et al., discovered a series of benzimidazole-2- urea derivatives as novel tubulin inhibitors. Among them, compound N-(6-(3-cyanophenoxy)- 1H-benzo[d]imidazol- 2- yl)- 2 methylhydrazinecarboxamide (20) suppressed the proliferation of a panel of human cancer cells with IC₅₀ ranging from 0.040 to 1.774µM. It also inhibited NCI-H460 spindles formation and induced cell cycle arrest at G 2/M phase.

21. Guan Q et al., prepared a series of novel benzimidazole carbamates bearing indole moieties which were connected with sulphur or selenium atoms. The compounds were evaluated for their antiproliferative activities against three human cancer cell lines; SGC-7901, A-549 and HT-1080. Methyl 5-[(1H-indol-3-yl)selanyl]-1H-benzoimida-zol-2-ylcarbamate (21) showed the most potent antitumour activity.

22. Yoon YK et al., designed and synthesized a series of novel benzimidazole derivatives as sirtuin inhibitors. Compound ethyl 2-(4-(dimethylamino) phenyl)-1-(2-hydroxyethyl)-1Hbenzo[d] imidazole-5-carboxylate (22) showed best inhibitory activity for SIRT 1 and SIRT 2 with IC₅₀ values of 58.43µM & 45.12µM respectively. It also showed good anti-tumor activity against different breast cancer cell lines.

23. Galal SA et al., synthesized novel benzimidazole -5- carboxylic acid derivatives and their transition metal-metal complexes with Cu^2+, Co²⁺, Zn²⁺. They were evaluated for their growth inhibitory activity against 21 human cancer cell lines. Among them, 1-((5(or 6)-carboxy-1Hbenzo [d] imidazol-2-yl)methyl)pyridinium copper(II) chloride hydrate (23) inhibited topoisomerase-II activities at 10 times lower concentration than etoposide.

24. Coban G et al., synthesized several benzimidazole derivatives with substitution at 2 & 5 positions. They were screened to identify if they interfered with mammalian type I DNA topoisomerase activity via in-vitro supercoil relaxation assays. Some compounds were subjected to cytostatic assays using various cancer cell lines. Results showed that 5-chloro-2(2-hydroxyphenyl)-1H-benzimidazole (24) exerted the most profound topoisomerase I inhibition and cytotoxicity.

25. Abdel-Aziz H A et al., developed a series of 2-((benzimidazol-2-yl)thio)- 1-arylethan- 1- ones as potent anti-tumor agent that target both cancer stem cells and the bulk of tumor cells. They were evaluated for their antiproliferative activity towards colon HT-29 cancer cell line. 2-((1H-benzo[d]imidazol-2-yl)thio)-1-(2, 3, 4-trimethoxy-phenyl)ethan-1-one (25) was the most active anti-proliferative analog with 50.11±4.05 % inhibition effect.

26. Gao C et al., have synthesized various benzimidazole acridine derivatives. These were evaluated as potential DNA binding and apoptosis-inducing agents. Amongst them N-((1Hbenzo(d) imidazole- 2- yl)methyl- 3- methylacridin-9-amine) (26) displayed good anti proliferative activity against both K-562 & HepG-2- cells.

Anti-Microbial Activity:

27. Seenaiah. D et al., prepared a variety of pyrimidinyl benzoxazoles, benzothiazoles, and benzimidazoles linked by thio, methylthio, and amino moieties. They were evaluated for their antimicrobial activity. The compound pyrimidinyl bis methylthio benzimidazole (27) was potent against Staphylococcus aureus (29 mm, MIC 12.5 mg/mL) and Penicillium chrysogenum (38 mm, MIC 12.5 mg/mL).

28. Zhang H et al., ²⁸ designed a series of benzimidazole type of fluconazole analogues & screened them for their anti-microbial activities. The compound 3,5-bis(trifluoromethyl)phenyl benzimidazole (28) displayed a stronger anti-bacterial and anti-fungal activity. The combination of 2,4-difluorobenzyl benzimidazole derivatives & its hydrochloride with antibacterial chloromycin showed broad spectrum activity.

29. Gowda J et al., ²⁹ synthesized a series of 1,3,4-oxadiazoles bearing benzimidazole moiety as antimicrobial agents. Compounds carrying benzyl group at the 2-position of the benzimidazole ring and electron releasing group on the phenyl groups showed significant activity. Among them 2-benzyl-1-{[5-(p-tolyl)-1, 3, 4-oxadiazol-2-yl] methyl}-1H benzimidazole (29) displayed good activity.

30. Gowda J et al., prepared a series of benzimidazole derivatives carrying quinolone moiety by one step process, which included nucleophilic substitution and cyclization. They were evaluated for their anti-bacterial activity. The compound with nitro group at the 5-position of the benzimidazole moiety; 2-(5-nitro-1H- benzimid-azole-2-yl) thieno [2,3-b]-quinoline (30) displayed good antibacterial activity.

31. Eisa HM et al., prepared a series of benzimidazole derivatives fused with oxadiazoles and triazoles. The synthesized compounds were screened for antimicrobial activity. Among them 1-[(5-methylthio-3,4-oxadiazol-2-yl)methyl]-2-benzyl-thio-1H-benzimidazole (31) exhibited significant activity.

32. Petkar K et al., prepared a series of 2-chloromethyl-1H-benzimidazole derivatives and screened them for their anti-fungal activity against Candida albicans.

Among the synthesized compounds, (1H-benzimidazole -2-ylmethyl)-(3-chloro- 4- fluoro- phenyl)- amine (32) showed significant activity with MIC value of 12.5 µg/ml.

33. Zhang D et al., designed and synthesized novel actinonin derivatives containing benzimidazole heterocycles and evaluated there in-vitro antibacterial activity. Among them, compound (R)-2-butyl-N4-hydroxy-N1- [1- (S)- (benzimidazol-2-yl)-2-methyl]propylsuccinamide (33) with an unsubstituted benzimidazole ring exhibited potent antibacterial activity with MIC 2 µg/ml, 0.5 µg/ml and 4 µg/ml against Staphylococcus aureus, Klebsiella pneumoniae, and Sarcina lutea respectively with comparison to the standard cefoperazone.

34. Tuncbilek M et al., synthesized novel benzimidazole derivatives and evaluated for antimicrobial activity. Compounds 5,6-dichloro-2-(4-fluorophenyl)-1H-benzimi-dazole,5,6dichloro-2-(4- chlorophenyl)- 1H-benzimidazole, 2- (4-t-butyl-phenyl)-5, 6-dichloro-1- Hbenzimidazole, which have no substitution of N-1 position displayed better antibacterial activity than those of standards (ciprofloxacin, ampicillin and sultamicillin) against both the drug-resistant bacteria (MRSA, standard and clinical isolates). While derivative 2-amino-5, 6-dichloro-1-cyclopentyl-1H-benzi-midazole (34) exhibited the most potent antibacterial activity with MIC 3.12 µg/ml against Staphylococcus aureus.

35. Vinodhkumar R et al., synthesized novel N-substituted-2-(4-phenylethynylphe-nyl)-1Hbenzi-midazoles and N-substituted 2[4-(4,4-dimethyl-thiochroman-6-yl-ethynyl)-phenyl)- 1H benzimida-zoles and screened them for their potential anti-bacterial agents. Compounds 2-(4phenylethyn-yl phenyl)-1H-benzimidazole (35a) 2-[4-(4,4-dimethyl-thiochroman-6-ylethynyl)-phen-yl]-1H-benzimida-zole (35b) 2-(4- phenylethynyl-pheny)-1-(toluene-4sulfonyl)-1H-benzimidazole (35c) showed complete inhibition against both S. aureus and S. typhimurium.

Angiotensin II Receptor Antagonist Activity:

36. Zhu W et al., synthesized some 5-nitro benzimidazole with 1,4-disubsituted or 1,5-disubsituted indole derivatives and screened them for their novel angiotensin II receptor antagonist activity. The results revealed that 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1yl)methyl)-1H-indol-1-yl)benzoic acid (36) displayed a high affinity for the angiotensin II type 1 receptor with IC50 value of 1.03 ± 0.26 nM.

37. Kaur N et al., designed and synthesized 5-alkylsulfamoyl benzimidazole derivatives as angiotensin II receptor antagonists. The in-vitro and in-vivo tests reveals 4´-[(2-butyl-5cyclohexyl-sulfamoyl-1H-benzimidazol-1-yl)methyl]biphen-yl -2-carboxylic acid (37) as the most promising compound.

38. Zhang J et al., designed and synthesized a series of 6-substituted carbamoyl benzimidazoles as new nonpeptidic angiotensin II AT1 receptor antagonists. The various pharmacological evaluation revealed compound N-(2-phenyl) propyl-1-[2´-(1 -H–tetrazol-5-yl)-1,1´-biphenyl4-yl]methyl-4-methyl-2-n-propyl-1H-benzimidazole-6-carboxamide (38) as an orally active AT1 receptor antagonist with low toxicity.

Analgesic Activity:

39. Srivastava S et al., synthesized a series of novel 2-phenylhydrazinomethyl derivatives substituted at the N- 1-position of benzimidazole nucleus. The compound were screened for analgesic activity; among them N-ethyl-N-({2-[(2-phenylhydrazinyl) methyl]-1Hbenzimidazole-1 yl}methyl) ethanamine (39) exhibited a promising activity when compared to the standard drug diclofenac sodium. The fusion of a phenylhydrazinomethyl nucleus at the 2-position of benzimidazole compound gave a biologically active pharmacophore.

40. Achar K C S et al., synthesized a series of 2-methylaminobenzimidazole derivatives by the reaction of 2-chloromethylbenzimidazole with different aromatic amines. These compounds were screened for analgesic and anti-inflammatory activities on acetic acid-induced writhing in mice and rats. Compound N-[(5-bromo-1H-benzimid-azol-2-yl) methyl]-3-chloroaniline (40) showed good result.

Anti-oxidant Activity:

41. Kus C et al., developed a series of thiadiazol-2-amine & triazole-3(4H)- thione derivatives of benzimidazole class. These were evaluated for their antioxidant properties. Compound 5-[(2- (chloro-phenyl)- 1H- benzimidazol-1-yl) methyl]-4-methyl-2H-1,2,4-triazole-3(4H)-thiones (41) inhibited the microsomal ethoxyresorufin-O-deethylase (EROD) activity with IC₅₀ of 4.5 × 10^-4M.

42. Taha M et al., have synthesized novel 4-Methylbenzimidazole derivatives. These were evaluated for their antioxidant activity. N'-(2,4-dihydroxybenzylidene)-4-(4-methyl-1Hbenzo[d] imidazol-2-yl)benzohydrazide (42) showed excellent antioxidant activity better than the standard n-propyl gallate with IC₅₀ value of 27.45 μM.

Miscellanous Activity:

43. Yang H et al., have discovered some benzimidazole analogues as phosphodiesterase 10A (PDE10A) inhibitors. (4-([3,3'-bipyridin]-2-yloxy) phenyl)(1- methyl- 1H- benzo[d]imidazol- 2yl) methanone (43) showed high potency & in vitro selectivity with IC₅₀ value of 3.73 nM.

44. Aslam S et al., developed novel hybrids of pyrazolobenzothiazine and benzimidazoles. The phenylene connected hybrid compounds were investigated as inhibitors of acetylcholinesterase (AChE). Compound 2-[4-(1H-benzimidazol-2-yl) phenyl]-4-methyl-3phenyl-2,4-dihydropyrazolo [4,3-c][1,2]benzothiazine 5,5-dioxide (44) was the most potent AChE inhibitor with IC₅₀ value of 11 nM.

45. Pérez-Villanueva J et al., synthesized a series of new 2-{[2-(1H-imidazol-1yl)ethyl]sulfanyl}-1H-benzimidazole derivatives (45). The novel compounds were tested against various species of protozoa; Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. The antiprotozoal evaluation revealed strong activity for all tested compounds, with IC₅₀ values in the nanomolar range, which were even better than the standard metronidazole drug.

46. Shingalapur R V et al., synthesized a group of 4-thiazolidinones containing 2- mercapto benzimid-azole moiety and evaluated them for in-vivo anticonvulsant activity by maximal electroshock (MES) model. 3-(1H-benzimidazol-2-ylsulfanyl-methyl)- 2- (2-hydroxy-phenyl)- thiazolidin-4-one (46) exhibited excellent anticonvulsant activity. The pharmacophore derived from active molecules suggests the presence of –OH group in all the active compounds.

47. Takahashi K et al.,.have designed a series of 2-(pyridine-2-yl )-1H- benzimidazole derivatives (47) and evaluated them as glucokinase activators. Among them, the potent activator exhibited good hypoglycemic activity.

48. Xue F et al., have synthesized a series of novel benzimidazole derivatives and evaluated for their antiviral activity. Strong activities against entero-virus were observed in these benzimidazoles. The most promising compound was (L)-2-(pyridin-2-yl)-N-(2-(4nitrophenyl)pentan-3-yl)-1H-benzimid-azole-4-carboxamide (48) with a high antiviral potency (IC₅₀ = 1.76 l μg/mL) and a remarkable selectivity index of 328.

49. Elshihawy H et al., have designed and synthesized various benzimidazole and quinoxaline derivatives as methionine synthase inhibitors. Compound N-((5nitro-1H-benzimidazole-2yl)methyl) benzamide (49) showed highest inhibition activity with IC₅₀ of 18μM.

50. Bansal Y et al., have reported various benzimidazole-ibuprofen/mesalamine conjugates and evaluated them for immunomodulatory activities. Among them 2-[(5-amino-2hydroxy)phenyl]benzi-midazole (50a) exhibited pronounced immuno-stimulatory and antiinflammatory effects and compound 2-[(5-amino-2-hydroxy)benzoylamino]-5–Nitrobenzimidazole (50b) showed maximum immunosuppressive response for various multi-factorial disorders.

51. Loudfy H. Makaur discovered the Inhibition of Corrosion of copper in nitric acid by benzimidazole and its derivatives. The inhibitive performance of seven synthesized 2-(2-benzimidazolyl)-4 (phenylazo) phenol (BPP_1–7) derivatives was investigated experimentally on the corrosion of copper in 2.0 M HNO₃ acid using mass loss, thermometric and DC potentiodynamic polarization techniques.

FIG. 1: VARIATION OF WEIGHT LOSS AGAINST TIME FOR COPPER CORROSION IN 2.0 M HNO₃ IN THE PRESENCE OF DIFFERENT CONCENTRATION OF BPP_1 AT 303 K

52. Elif Apohan synthesized fourteen novel cobalt (II) or zinc (II) complexes of benzimidazoles from the 1-(4-substitutedbenzyl)-1H-benzimidazoles and CoCl₂.6H₂O or ZnCl₂. Cytotoxic activities of novel complexes were investigated against lung cancer cells (A549) and BEAS-2B.

53. Mohammad Nikpassand has synthesised novel azo-linked 2-phenyl benzimidazoles using ionic liquid. In this research, novel series of benzimidazoles were synthesized using the reaction between various synthetized salicylaldehydes, and naphthalene2,3-diamine or 1,2-diaminobenzene in the presence of a catalytic amount of 3,3-(butane-1, 4diyl)bis(1, 2-dimethyl- 1H-imidazole-3-ium)Br by a one-pot procedure without additional organic solvents and oxidants.

In conclusion, he has developed a simple, convenient and efficient protocol for the synthesis of 2-phenyl benzimid-azoles using ionic liquid as an efficient catalyst [BDBDMIm]Br. The simplicity, easy workup, together with the use of inexpensive, environ-mentally friendly, and reusable catalyst, is the notable features of this catalytic procedure. To the best of knowledge, this is the first report for the synthesis of a new library of benzimidazole compounds bearing azo linkage moiety that enhances the biological activity.

54. Lianhai Yau has synthesized tricyclic benzimidazole-iminosugars as potential glycol-sidase inhibitors via a Mitsunobu reaction. A series of tricyclic benzimidazole-iminosugars 1(a-f) and 2(a-f) were constructed through the intramolecular cyclization of NH and OH by the key Mitsunubo reaction, providing an effective protocol for the preparation of the tricyclic iminosugars. Three compounds derived from D-ribose exhibited specific and good inhibitory effects on β-glucosidase.

CONCLUSION: It can be concluded from the present review study that Benzimidazole is a very promosing hetrocyclic ring structure possessing various activities and I believe that more studies such as DNA interaction studies, metal complex chelation and in-vivo animal studies can be carried out this versatile moiety.

ACKNOWLEDGEMENT: The author acknow-ledges Principal KLE College of Pharmacy, Belagavi for providing the facilities and my students Mr. Varun and Ms. Shreya, who extensively searched the data available on Benzimidazoles.

CONFLICTS OF INTEREST: The authors confirm that the contents of this review article bear no conflict of interest.

REFERENCES:

1. Narasimhan B, Sharma D and Kumar P: Benzimidazole: a medicinally important heterocyclic moiety. Med Chem Res 2012; 21: 269-83.
2. Olender D, Żwawiak J, Lukianchuk V, Lesyk R, Kropacz A, Fojutowski A and Zaprutko L: Synthesis of some N-substituted nitroimidazole derivatives as potential antioxidant and antifungal agents. European Journal of Medicinal Chemistry. 2009; 44(2): 645-52.
3. Singh J, Grover P and Pathak DP: Synthesis, anticonvulsant activity and comparative QSAR study of some novel 1, 2, 5-trisubstituted benzimidazole derivatives. Acta Pharmaceutica Sciencia 2010; 52(4).
4. Gupta P, Hameed S and Jain R: Ring-substituted imidazoles as a new class of anti-tuberculosis agents. European Journal of Medicinal Chemistry 2004; 39(9): 80514.
5. Shingalapur RV, Hosamani KM and Keri RS: Synthesis and evaluation of in-vitro anti-microbial and anti-tubercular activity of 2-styryl benzimidazoles. European Journal of Medicinal Chemistry 2009; 44(10): 4244-8.
6. Pandey J, Tiwari VK, Verma SS, Chaturvedi V, Bhatnagar S, Sinha S, Gaikwad AN and Tripathi RP: Synthesis and antitubercular screening of imidazole derivatives. European Journal of Medicinal Chemistry 2009; 44(8): 3350-5.
7. Hadizadeh F, Hosseinzadeh H, Motamed-Shariaty VS, Seifi M and Kazemi SH: Synthesis and antidepressant activity of N-substituted imidazole-5-carboxamides in forced swimming test model. Iranian Journal of Pharmaceutical Research 2010; 20(1): 29-33.
8. Naik P, Murumkar P, Giridhar R and Yadav MR: Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists-A perspective. Bioorganic & Medicinal Chemistry 2010; 18(24): 8418-56.
9. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM and Wienen W: Structure-based design of novel potent nonpeptide thrombin inhibitors. Journal of Medicinal Chemistry 2002; 45(9): 1757-66.
10. Lee JG, Shin JH, Shim HS, Lee CY, Kim DJ, Kim YS and Chung KY: Autophagy contributes to the chemo-resistance of non-small cell lung cancer in hypoxic conditions. Respiratory Research 2015; 16(1): 138.
11. Yurdakul AS, Kocatürk C, Bayiz H, Gürsoy S, Bircan A, Özcan A, Akkoçlu A, Uluorman F, Çelik P, Köksal D and Ulubaş B: Patient and physician delay in the diagnosis and treatment of non-small cell lung cancer in Turkey. Cancer Epidemiology 2015; 39(2): 216-21.
12. Giannopoulou E, Nikolakopoulos A, Kotsirilou D, Lampropoulou A, Raftopoulou S, Papadimitriou E, Theocharis AD, Makatsoris T, Fasseas K and Kalofonos HP: Epidermal growth factor receptor status and Notch inhibition in non-small cell lung cancer cells. Journal of Biomedical Science 2015; 22(1): 98.
13. Clark DJ, Mei Y, Sun S, Zhang H, Yang AJ and Mao L: Glycoproteomic approach identifies KRAS as a positive regulator of CREG1 in non-small cell lung cancer cells. Theranostics 2016; 6(1): 65.
14. Farha AK, Dhanya SR, Mangalam SN and Remani P: Anti-metastatic effect of deoxyelephantopin from Elephantopus scaber in A549 lung cancer cells in-vitro. Natural Product Research 2015; 29(24): 2341-5.
15. Ahn MY, Kim TH, Kwon SM, Yoon HE, Kim HS, Kim JI, Kim YC, Kang KW, Ahn SG and Yoon JH: 5-Nitro-5′-hydroxy-indirubin-3′-oxime (AGM130), an indirubin-3′-oxime derivative, inhibits tumor growth by inducing apoptosis against non-small cell lung cancer in vitro and in vivo. European Journal of Pharmaceutical Sciences 2015; 79: 122-31.
16. Greve G, Schiffmann I and Lübbert M: Epigenetic priming of non-small cell lung cancer cell lines to the antiproliferative and differentiating effects of all-trans retinoic acid. Journal of Cancer Research and Clinical Oncology 2015; 141(12): 2171-80.
17. Lewis KM, Bharadwaj U, Eckols TK, Kolosov M, Kasembeli MM, Fridley C, Siller R and Tweardy DJ: Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer. Lung Cancer 2015; 90(2): 182-90.
18. Zhao J, Fu W, Liao H, Dai L, Jiang Z, Pan Y, Huang H, Mo Y, Li S, Yang G and Yin J: The regulatory and predictive functions of miR-17 and miR-92 families on cisplatin resistance of non-small cell lung cancer. BMC Cancer 2015; 15(1): 1-4.
19. Şırecı N, Küçükbay H, Akkurt M, Pinar Yalçin Ş, Nawaz Tahır M and Ott H: Preparation and characterization of trimethylsilyl-substituted benzimidazole metal complexes and structural characterization of dichlorobis [1-(trimethylsilyl) methyl-1 H-benzimidazole-κ N 3] cobalt (II). Journal of Coordination Chemistry 2010; 63(18): 3218-28.
20. Sireci N, Yilmaz Ü, Küçükbay H, Akkurt M, Baktir Z, Turktekin S and Buyukgungor O: Synthesis of 1-substituted benzimidazole metal complexes and structural characterization of dichlorobis (1-phenyl-1H-benzimidazole-kappa N-3) cobalt (II) and dichlorobis (1-phenyl-1H-benzimidazole-kappa N-3) zinc (II).
21. Kuçukbay H, Yilmaz U, Akkurt M, Büyükgungor O. Synthesis and characterization of substituted benzimidazole Co (II), Fe (II), and Zn (II) complexes and structural characterization of dichlorobis {1-[2-(1-piperidinyl) ethyl]-1H-benzimidazole-_KN^ 3} zinc (II). Turkish Journal of Chemistry 2015; 39(1): 108-20.
22. Kuçukbay H, Mumcu A, Tekin S and Sandal S: Synthesis and evaluation of novel N, N'-disubstituted benzimidazolium bromides salts as antitumor agents. Turkish Journal of Chemistry 2016; 40(3): 393-401.
23. Xia Q, Chen W and Qiu H: Direct C–N coupling of imidazoles and benzylic compounds via iron-catalyzed oxidative activation of C–H bonds. The Journal of Organic Chemistry 2011; 76(18): 7577-82.
24. Wan Y, Wallinder C, Plouffe B, Beaudry H, Mahalingam AK, Wu X, Johansson B, Holm M, Botoros M, Karlén A and Pettersson A: Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist. Journal of Medicinal Chemistry 2004; 47(24): 5995-6008.
25. Vasantha VA, Jana S, Parthiban A and Vancso JG: Water swelling, brine soluble imidazole based zwitterionic polymers–synthesis and study of reversible UCST behaviour and gel–sol transitions. Chemical Communications 2014; 50(1): 46-8.
26. Demarse NA, Ponnusamy S, Spicer EK, Apohan E, Baatz JE, Ogretmen B and Davies C: Direct binding of glyceraldehyde 3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation. Journal of Molecular Biology 2009; 394(4): 789-803.
27. Gokbulut AA, Apohan E and Baran Y: Resveratrol and quercetin-induced apoptosis of human 232B4 chronic lymphocytic leukemia cells by activation of caspase-3 and cell cycle arrest. Hematology 2013; 18(3): 144-50.
28. Wu H, Yuan J, Bai Y, Pan G, Wang H, Shao J, Gao J and Wang Y: Synthesis, crystal structure, DNA-binding properties, and antioxidant activity of a V-shaped ligand bis (N-methylbenzimidazol-2-ylmethyl) benzylamine and its zinc (II) complex. Journal of Coordination Chemistry 2012; 65(24): 4327-41.
29. Poyraz M, Sarı M, Gueney A, Demirci F, Demirayak S and Şahin E: Synthesis, characterization and antimicrobial activity of a Zn (II) complex with 1-(1H-benzoimidazol-2-yl)-ethanone thiosemicarbazone. Journal of Coordination Chemistry 2008; 61(20): 3276-83.
30. Yurttas L, Demirayak S and Ciftci GA: Cytotoxic, antiproliferative and apoptotic effects of new benzimidazole derivatives on A549 lung carcinoma and C6 glioma cell lines. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 2015; 15(9): 1174-84.
31. Liu S, Cao W, Yu L, Zheng W, Li L, Fan C and Chen T: Zinc (II) complexes containing bis-benzimidazole derivatives as a new class of apoptosis inducers that trigger DNA damage-mediated p53 phosphorylation in cancer cells. Dalton Transactions 2013; 42(16): 5932-40.
32. Błaszczak-Swiątkiewicz K, Olszewska P and Mikiciuk-Olasik E: Biological approach of anticancer activity of new benzimidazole derivatives. Pharmacological Reports 2014; 66(1): 100-6.
33. El-Sherif AA: Synthesis, solution equilibria and antibacterial activity of Co (II) with 2-(aminomethyl)-benzimidazole and dicarboxylic acids. Journal of solution chemistry 2010; 39(10): 1562-81
34. Asekunowo PO, Haque RA, Razali MR and Budagumpi S: Benzimidazole‐based silver (I)–N‐heterocyclic carbene complexes as anti‐bacterials: synthesis, crystal structures and nucleic acids interaction studies. Applied Organometallic Chemistry 2015; 29(3): 126-37.
35. Podunavac-Kuzmanović SO, Leovac VM, Cvetković DD. Antibacterial activity of cobalt (II) complexes with some benzimidazole derivatives. Journal of the Serbian Chemical Society 2008; 73(12): 1153-60
36. Singh AK and Lown JW: Design, Synthesis and antitumor cytotoxicity of novel bis benzimidazoles. Anti-cancer Drug 2000; 15: 265.
37. Lukevics E, Arsenyan P, Shestakova I, Domracheva I, Nesterova A and Pudova O: Synthesis and antitumour activity of trimethylsilylpropyl substituted benzimidazoles. Eur J Med Chem 2001; 36: 507.
38. Srikanth L, Raghunandan N and Sambasiva R: Synthesis, antimicrobial and anthelmintic activity of some novel benzimidazole derivatives. Der Pharma Chemica 2011; 3: 344.
39. Sreena K, Ratheesh R, Rachana M, Poornima M and Shyni C: Synthesis and anthelmintic activity of benzimidazole derivatives. Hygei 2009; 1: 21.
40. Jun C, Jiangtao X and Xianjin L: Synthesis and antiviral activity against Coxsackie virus B3 of some novel benzimidazole derivatives. Bioorg Med Chem Lett 2005; 15: 267.
41. Ashish KT and Anil M: Synthesis and antiviral activities of N-substituted-2-substituted benzimidazole derivatives. Ind J Chem 2006; 45: 489.
42. Carlsson E, Lindberg P and Unge S: Two of a kind. Chem Britain 2002; 5: 42.
43. Gulgun AK and Nurten A: Synthesis and antifungal properties of some benzimidazole derivatives. Turk J Chem 2006; 30: 223.
44. Maxwell WA and Brody G: Antifungal activity of selected benzimidazole compounds. App Microbiol 1971; 21: 944.
45. Lazer ES, Matteo MR and Possanza GJ: Benzimidazole derivatives with atypicalantiinflammatory activity. J Med Chem 1987; 30: 726.
46. Hassan ME, Alaa-eldin MB, Sahas MB and Farahat AA: Synthesis and antimicrobial activity of certain benzimidazole and fused benzimidazole derivatives. Ind J Chem 2010; 49: 1515.
47. Gulgu AK and Nurten A: Synthesis and antimicrobial activities of new benzimidazole derivatives. IL Farmaco 2003; 58: 1345.
48. Haugwitz RD: Anti-parasitic agents Synthesis and anti-helmintic activities of novel 2 substituted isothiocya-natobenzoxazoles and benzimidazole. J Med Chem 1982; 25: 969.
49. Grassi A, Ippen J, Bruno M, Thomas G and Bay P: A thiazolylamino benzimidazole derivative with gastroprotective properties in therat. Eur J Pharmacol 1991; 195: 251.
50. Ozkay Y, Tunali Y, Karaca H and Isikdag I: Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazones moiety. European J Med Chem 2010; 45: 3293.
51. Kalidhar U and Kaur A: An Overview on Some Benzimidazole and Sulfonamide Derivatives with Anti-Microbial Activity. Res J Pharmal Biolog Chem Sci 2011; 2: 1116.
52. Reddy CS and Nagraj A: A mild, efficient and one pot synthesis of 2-substituted benzimidazoles by ZrOCl₂.8H₂O catalyzed ring closure reactions. Ind J Chem 2008; 47: 1154.
53. Kumar R and Joshi YC: Mild and Efficient One Pot Synthesis of Imidazolines and Benzimidazoles from Aldehydes. E-J. Chem 2007; 4: 606.
54. Javanshir S and Farnia S: A facile three-component one pot solvent-free synthesis of 2'aminobenzimidazolo-methylnaphtols. 14^th Electro. Confer Syn Org Chem (ECSOC-14) 2010.
55. Khan AT, Parvin T and Choudhury LH: A Simple and Convenient One-Pot Synthesis of Benzimidazole Derivatives Using Cobalt(II) Chloride Hexahydrate as Catalyst Cheminform 2009; 40: 2339.
56. Perumal S, Mariappan S and Selvaraj S: A microwave assisted synthesis of 2-aryl-1 arylmethyl-1H-1,3-benzimidazoles in the presences of K-10. Arkivoc 2004; 8: 46.
57. Nikpassand M, Zare L and Saberi M: Ultrasound-assisted L-proline catalyzed synthesis of novel derivatives of azo-linked dihydropyridines. Monatsh Chem 2012; 143: 289.
58. Nikpassand M, Zare L, Changiz N and Imani F: Synthesis of New 3-Cyanocoumarins with C-6 Azo Function Using Ultrasound and Grinding Techniques in the Presence of NanoFe₃O₄. Lett Org Chem 2014; 11: 29.
59. Nikpassand M, Zare Fekri L, Karimian L and Rassa M: Synthesis of biscoumarin derivatives using nanoparticle Fe₃O₄ as an efficient reusable heterogeneous catalyst in aqueous media and their antimicrobial activity. Curr Org Chem 2015; 12: 358.
60. Nikpassand M, Zare Fekri L and Farokhian P: An efficient and green synthesis of novel benzoxazole under ultrasound irradiation. Ultrason Sonochem 2016; 28: 341.
61. Stutz AE: Iminosugars as glycosidase inhibitors, nojirimycin and beyond. Weinheim: Wiley-VCH; 1999.
62. Sattin S, Bernardi A. Design and synthesis of glycomimetics.
63. Saliba RC and Pohl NL: Designing sugar mimetics: non-natural pyranosides as innovative chemical tools. Current Opinion in Chemical Biology 2016; 34: 127-34.
64. Yan L, Lui H, Sun J, Gao L, Lu X, Li X and Chen H: Synthesis of tricyclic benzimidazole-iminosugars as potential glycosidase inhibitors via a Mitsunobu reaction. Carbohydrate Research 2019; 485: 107807.
65. Varrot A, Tarling CA, Macdonald JM, Stick RV, Zechel DL, Withers SG and Davies GJ: Direct observation of the protonation state of an imino sugar glycosidase inhibitor upon binding. Journal of the American Chemical Society 2003; 125(25): 7496-7.
66. Guce AI, Clark NE, Salgado EN, Ivanen DR, Kulminskaya AA, Brumer H and Garman SC: Catalytic mechanism of human α-galactosidase. Journal of Biological Chemistry 2010; 285(6): 3625-32.
67. Compain P and Martin OR: Iminosugars: From synthesis to therapeutic applications. John Wiley & Sons 2007.
68. Kiappes JL, Hill ML, Alonzi DS, Miller JL, Iwaki R, Sayce AC, Caputo AT, Kato A and Zitzmann N: ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting antiflaviviral activity. ACS Chemical Biology 2018; 13(1): 60-5.
69. Lillelund VH, Jensen HH, Liang XF and Bols M: Chem Rev 2002; 102: 515-53.
70. Gloster TM and Davies GJ: Glycosidase inhibition: assessing mimicry of the transition state. Organic & Biomolecular Chemistry 2010; 8(2): 305-20.
71. Sanchez-Fernandez EM, Gonçalves-Pereira R, Rísquez-Cuadro R, Plata GB, Padrón JM, Fernández JM and Mellet CO: Influence of the configurational pattern of sp2-iminosugar pseudo N-, S-, O-and C-glycosides on their glycoside inhibitory and antitumor properties. Carbohydrate Research 2016; 429: 113-22.
72. Mena-Barragan T, Narita A, Matias D, Tiscornia G, Nanba E, Ohno K, Suzuki Y, Higaki K, Garcia Fernandez JM and Mellet CO: pH responsive pharmacological chaperones for rescuing mutant glycosidases. Angewandte Chemie 2015; 127(40): 11862-6.
73. Garcia-Moreno MI, de la Mata M, Sánchez-Fernández EM, Benito JM, Díaz-Quintana A, Fustero S, Nanba E, Higaki K, Sánchez-Alcázar JA, Fernandez JMG and Mellet CO: Fluorinated Chaperone− β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease. Journal of Medicinal Chemistry 2017; 60(5): 1829-42.
74. Sanchez-Fernandez EM, Fernandez JM and Mellet CO: Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: Lessons from Gaucher, G M1-gangliosidosis and Fabry diseases. Chemical Communications 2016; 52(32): 5497-515.
75. Mena-Barragan T, Garcia-Moreno MI, Nanba E, Higaki K, Concia AL, Clapés P, Fernández JM and Mellet CO: Inhibitor versus chaperone behaviour of d-fagomine, DAB and LAB sp2-iminosugar conjugates against glycosidases: A structure–activity relationship study in Gaucher fibroblasts. European Journal of Medicinal Chemistry 2016; 121: 880-91.
76. Mena-Barragan T, Garcia-Moreno MI, Sevsek A, Okazaki T, Nanba E, Higaki K, Martin NI, Pieters RJ, Fernandez JM and Mellet CO: Probing the inhibitor versus chaperone properties of SP2-iminosugars towards human β-glucocerebrosidase: A picomolar chaperone for Gaucher disease. Molecules 2018; 23(4): 927.
77. Risquez-Cuadro R, Matsumoto R, Ortega-Caballero F, Nanba E, Higaki K, Garciia Fernaandez JM and Ortiz-Mellet C: Pharmacological Chaperones for the Treatment of α-Mannosidosis. Journal of Medicinal Chemistry 2019; 62(12): 5832-43.
78. Alcalde-Estévez E, Arroba AI, Sánchez-Fernández EM, Mellet CO, Fernández JM, Masgrau L and Valverde ÁM: The sp2-iminosugar glycolipid 1-dodecylsulfonyl-5N, 6O-oxomethylidenenojirimycin (DSO2-ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv. 2 microglial cells and retinal explants. Food and Chemical Toxicology 2018; 111: 454-66.
79. Prasad SS, Reddy NR and Baskaran S: One-Pot Synthesis of Structurally Diverse Iminosugar-Based Hybrid Molecules. The Journal of Organic Chemistry 2018; 83(17): 9604-18.
80. Yadav LD and Awasthi C: Efficient one-pot synthetic protocols for iminosugar-bearing imidazo [1, 2-a] pyridines from carbohydrates. Carbohydrate Research 2010; 345(2): 318-23.
81. Cordero FM, Khairnar BB, Bonanno P, Martinelli A and Brandi A: Copper Catalyzed Synthesis of a Highly Hydroxy Functionalized Benzo [e] indolizidine by Intramolecular N Arylation. European Journal of Organic Chemistry 2013; 2013(22): 4879-86.
82. Iwata M, Kamijoh Y, Yamamoto E, Yamanaka M and Nagasawa K: Total Synthesis of Pyrrole–Imidazole Alkaloid (+)-Cylindradine B. Organic letters 2017; 19(2): 420-3.
83. Shao J, Zhu M, Gao L, Chen H and Li X: Synthesis of tetracyclic azasugars fused benzo [e][1, 3] thiazin-4-one by the tandem Staudinger/aza-Wittig/cyclization and their HIV-RT inhibitory activity. Carbohydrate Research 2018; 456: 45-52.
84. Yan L, Yin Z, Niu L, Shao J, Chen H and Li X: Synthesis of pentacyclic iminosugars with constrained butterfly-like conformation and their HIV-RT inhibitory activity. Bioorg & Medicinal Chemistry Letters 2018; 28(3): 425-8.
85. Sun J, Kang Y, Gao L, Lu X, Ju H, Li X and Chen H: Synthesis of tricyclic quinazolinone-iminosugars as potential glycosidase inhibitors via a Mitsunobu reaction. Carbohydrate Research 2019; 478: 10-7.
86. Akhtar W, Khan MF, Verma G, Shaquiquzzaman M, Rizvi MA, Mehdi SH, Akhter M and Alam MM: Therapeutic evolution of benzimidazole derivatives in the last quinquennial period. European Journal of Medicinal Chemistry 2017; 126: 705-53.
87. Bansal Y and Silakari O: The therapeutic journey of benzimidazoles: a review. Bioorganic & Medicinal Chemistry 2012; 20(21): 6208-36
88. Adegboye AA, Khan KM, Salar U, Aboaba SA, Chigurupati S, Fatima I, Taha M, Wadood A, Mohammad JI, Khan H and Perveen S: 2-Aryl benzimidazoles: Synthesis, In-vitro α-amylase inhibitory activity, and molecular docking study. European Journal of Medicinal Chemistry 2018; 150: 248-60.
89. Özil M, Parlak C and Baltaş N: A simple and efficient synthesis of benzimidazoles containing piperazine or morpholine skeleton at C-6 position as glucosidase inhibitors with antioxidant activity. Bioorganic Chemistry 2018; 76: 468-77.
90. Liu D, Zheng H, Yang W and Chen Y: Efficient removal of Sr (II) from aqueous solution by melamine-trimesic acid modified attapulgite composite. Journal of Radioanalytical and Nuclear Chemistry 2019; 321(1): 97-108.
91. Sallam MAE, Waagen V and Anthonsen T: Carbohydr Res 2008; 343: 388-91.
92. Fletcher S: The Mitsunobu reaction in the 21^st Organic Chemistry Frontiers 2015; 2(6): 739-52
93. Beddoe RH, Sneddon HF and Denton RM: The catalytic Mitsunobu reaction: a critical analysis of the current state-of-the-art. Organic & Biomolecular Chemistry 2018; 16(42): 7774-81.
    

    ---

    How to cite this article:

    Saxena A, Hegde V, Mutalikdesai S and Maste M: Versatility of benzimidazole and its derivatives; an insight. Int J Pharm Sci & Res 2020; 11(9): 4152-73. doi: 10.13040/IJPSR.0975-8232.11(9).4152-73.

    ---

    All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---