Exploring the anti-microbial potential of benzylated imidazolium salts: synthesis, docking studies, and biological evaluation

Abstract

Dibenzyl methyl-substituted imidazolium salts were synthesized from readily available starting materials using conventional methods. Initially, benzyl bromide derivatives were employed to alkylate 2-methyl-5-nitroimidazole under reflux conditions, yielding mono-, di-, and tri-meric imidazolium salts in high yields. Subsequent anion–exchange reactions produced compounds with yields of 83–89%, while solid-phase, silica-supported processes further enhanced yields to 89–96%. The antibacterial activity of these compounds against six human pathogens (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris, Staphylococcus aureus, and Enterococcus faecalis) was evaluated using well diffusion and broth microdilution techniques. Notably, nitro-substituted imidazolium salts demonstrated significant antibacterial activity, with bromide variants exhibiting the strongest inhibition. Minimum inhibitory concentration values revealed potent bactericidal effects. In terms of ADMET properties, all synthesized compounds exhibited favorable profiles, including good gastrointestinal absorption, skin permeation, and minimal inhibitory effects on key cytochrome P450 enzymes. Molecular docking analysis revealed significant binding affinities, particularly for compounds 4 and 6, with bacterial proteins, highlighting key interactions such as hydrogen bonding and π-alkyl stacking. Molecular dynamic simulations of top compounds against bacterial target proteins exhibited stable interactions and conformations throughout 100 ns trajectories. These synthesized compounds showed promising antibacterial properties, warranting further investigation for potential therapeutic applications.