Structure-based Design and Pharmacological Profiling of Triphenyl Imidazole Derivatives as Multi-target Antimicrobial Candidates

Abstract

The rising incidence of antimicrobial resistance necessitates the development of novel agents capable of acting on multiple microbial targets. Imidazole-based heterocycles are well recognized for their broad-spectrum antimicrobial properties. In this context, the present study focuses on the structure-based design and evaluation of a new series of 2,4,5-triphenyl imidazole derivatives as potential multi-target antimicrobial agents. A series of 2,4,5-triphenyl imidazole analogues was synthesized via a PEG-400–mediated condensation reaction involving benzil, substituted benzaldehydes, and ammonium acetate, followed by substitution with secondary amines. The synthesized compounds were structurally characterized using Fourier-transform Infrared (FTIR) spectroscopy and proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy. Antimicrobial activity was assessed using the agar diffusion method against Staphylococcus aureus and Escherichia coli as representative bacterial strains, and Candida albicans and Aspergillus niger as fungal strains. Molecular docking studies were performed against DNA gyrase B, dihydrofolate reductase, CYP51 lanosterol 14α- demethylase, and topoisomerase IIα. In silico ADMET profiling was conducted to evaluate pharmacokinetic and toxicity parameters. Among the synthesized derivatives, compound PARS-10 exhibited the highest antibacterial activity, producing a zone of inhibition of 15 mm against Staphylococcus aureus. Molecular docking studies revealed that compounds PARS-1, PARS-5, and PARS-7 showed strong binding affinities for key microbial targets, indicating their potential multitarget inhibitory activity. ADMET predictions suggested that most compounds were non-hepatotoxic, with several derivatives complying with Lipinski’s rule of five. The observed antimicrobial activity is attributed to the presence of the 2,4,5-triphenyl imidazole core, which facilitates effective interactions with multiple microbial enzymes. The docking results support the experimental findings and highlight the capability of selected compounds to simultaneously engage bacterial and fungal targets. Favorable ADMET properties further enhance the potential of these compounds as drug-like candidates. This study demonstrates that 2,4,5-triphenyl imidazole derivatives represent promising scaffolds for the development of novel multi-target antimicrobial agents. The combined in vitro, in silico, and ADMET results suggest that selected compounds exhibit potent antimicrobial activity and acceptable pharmacokinetic properties, warranting further optimization and biological evaluation.