Synthesis, Characterization and Molecular Docking Studies of Novel N-(benzimidazol-1-ylmethyl)-4-chlorobenzamide Analogues for Potential Anti-inflammatory and Antimicrobial Activity

Abstract

Background: The benzimidazole ring is an important pharmacophore in modern drug discovery. Mannich reaction is one of the versatile reaction widely used in organic synthesis. Mannich base derivatives play an important role in medical field with diverse biological actions.

Objective: A series of N-(benzimidazol-1-ylmethyl)-4-chlorobenzamide derivatives (3a- 3m) were synthesized and evaluated for anti-inflammatory and antimicrobial potential.

Method: Mannich reaction was used to synthesize N-(benzimidazol-1-ylmethyl)-4- chlorobenzamide analogues. The structures of novel target compounds were elucidated by spectral and analytical techniques and screened for in vivo anti-inflammatory activity and ulcerogenic activity. In addition, the prepared derivatives were also evaluated for in vitro antimicrobial activity against gram negative, gram positive and fungal strains. Further, in silico studies were carried out to define the interaction of the title compounds with COX-2 enzyme and microbial protein.

Results: The results revealed that out of thirteen molecules, compound 3a (containing chloromethyl substituent at 2-position of benzimidazole) showed significant antiinflammatory effect at a dose of 100 mg/kg p.o. and the experimental data was statistically significant at p≤0.05 level. Diclofenac sodium was taken as standard drug for antiinflammatory activity. Furthermore, derivative 3e (containing 2-chlorophenyl moiety at 2- position of benzimidazole scaffold) was found to be the most effective antimicrobial compound among the synthesized derivatives. Ciprofloxacin and clotrimazole were used as reference antimicrobial agents. Results from in vivo and in vitro studies of synthesized analogues were found to be in good correlation with in silico study.

Conclusion: These results designate that N-(Benzimidazol-1-ylmethyl)-4-chlorobenzamide analogues, substituted with halogen functionality, could be used as potential lead for designing more potent anti-inflammatory and antimicrobial agents.

Keywords: Anti-inflammatory activity; antimicrobial activity; benzimidazole; mannich bases; molecular docking study..