N-benzylimidazoles as potential antimicrobial and antibiofilm agents – syntheses, bioactivity and molecular docking studies

Abstract

Biofilm formation has been identified as one of the major pathways by which pathogens evade the effect of antimicrobial agents, leading to drug resistance in general. The imidazole ring provides a promising scaffold for the design of viable antimicrobial agents. In this work, halogenated benzyl derivatives of imidazole were synthesized and evaluated for antimicrobial and anti-biofilm activity. Molecular docking was used to analyse interactions between the compounds and the transcriptional regulator protein, LasR - a major protein that has downstream effect on biofilm formation in Pseudomonas aeruginosa. Results from the study revealed the marked potency of the halogenated compounds as antimicrobial agents. Antimicrobial susceptibility tests showed that the bromo- derivatives were very active against Gram-positive bacteria. The chloro- derivatives, on the other hand portrayed, a broad spectrum of antimicrobial activity. Notably, N-2-chlorobenzyl imidazole appeared to be the most potent antimicrobial agent with an MIC of 0.250 mg/mL against P. aeruginosa. Despite the relatively low antimicrobial effects displayed by the fluoro- derivatives, N-3-fluorobenzyl imidazole was identified to be a very good anti-biofilm agent with 5.3 µg/mL of the compound needed to inhibit biofilm formation by 50% (BIC50). Furthermore, all the compounds inhibited biofilms produced by Pseudomonas aeruginosa at sub-MIC concentrations. Predictions from molecular docking studies suggest that the compounds may not target the LasR protein in eliciting their anti-biofilm property.

Keywords

• LasR
• Pseudomonas aeruginosa
• Imidazoles
• Halogenated compounds
• Minimum inhibitory concentrations
• In silico analyses