Design, synthesis, antimicrobial evaluation, and molecular dynamics-based computational investigation of novel...

Antimicrobial resistance (AMR) continues to challenge global healthcare by reducing the effectiveness of existing antibacterial therapies. Resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) pose significant therapeutic challenges, underscoring the need for new antimicrobial candidates with improved antibacterial potential. The present study aimed to design, synthesize, characterize, and biologically evaluate a series of novel imidazole-thiol conjugates containing aminopyridine, chlorinated aromatic, nitroaromatic, and heteroaromatic moieties. The chemical structures of the synthesized compounds were characterized using FTIR, ¹H NMR, ¹³C NMR, and mass spectrometry. The synthesized derivatives exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria, including resistant strains such as MRSA and VRE. Among the synthesized derivatives, BS2 and BS3 exhibited the lowest minimum inhibitory concentration (MIC) values against the tested resistant strains. Computational studies, including molecular docking against Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI; PDB ID: 4ALL), molecular dynamics (MD) simulations, and MM/GBSA analyses, supported the predicted interaction of BS3 with the active site of SaFabI under the simulated conditions. In addition, BS3 exhibited moderate antioxidant activity, protected plasmid DNA against oxidative damage in the Fenton reagent-mediated DNA nicking assay, and demonstrated concentration-dependent cytotoxicity with acceptable cell viability at lower concentrations. In silico ADMET and toxicity analyses indicated acceptable drug-like and toxicity characteristics. Overall, BS3 was identified as a potential lead compound for further optimization as an antimicrobial agent.