Investigating the antibacterial potential of thiophene derivatives against wound infections: a combined DFT, molecular docking, and ADMET study targeting Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli resistant genes

Wound infection poses a significant global health threat, as it is a leading cause of morbidity and mortality among surgical patients and individuals with burn injuries, resulting in substantial healthcare burdens and devastating outcomes worldwide. Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli have frequently been implicated as major pathogens causing wound infections. This has eventually and consistently given rise to antimicrobial resistance divulging a need to mitigate infectious outbreaks. Herein, we employed a computational density functional theory (DFT) method at ωB97XD/6-311++g(d, p) level of theory to evaluate the performance of the thiophene derivative 5-(4-bromo-5-(methylthio)thiophen-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol 4, which is experimentally synthesized into five compounds (4a, 4b, 4c, 4d, and 4e). The chemical reactivity, kinetic stability, nature of interactions and functional characteristics of the thiophene derivatives were ascertained. The resistance gene PDB ID: 1K25, 2D45, 4UOT, and 7K2X were employed and docked with thiophene derivatives. Interestingly, molecular docking analysis demonstrated that ligands 4a, 4b, 4c, 4d, and 4e are more effective against proteins 1K25, 4U0T and 7K2X than amoxicillin and methicillin. Upon docking with the 2D45 protein, compounds 4c and 4e (− 5.9 kcal/mol) exhibited potential similar to that of methicillin (− 5.9 kcal/mol), while 4a and 4b showed slightly better affinities (− 6.1 kcal/mol and 6.0 kcal/mol). Using Lipinski's Rule of Five (Ghose filter, Veber rules, Muegge filter, and Egan's rule), 4d and 4e were determined to be the most promising candidates for drug development due to their compliance with all evaluated criteria, indicating favourable properties for oral bioavailability and drug likeness. This research suggested that thiophene derivatives can serve as promising antibacterial agents against wound-infected bacteria.