Design synthesis and antibacterial evaluation of naphthyl sulfonamide derivatives supported by computational and experimental studies

Abstract The rising global crisis of antibiotic resistance demands innovative strategies for discovering novel antimicrobial agents. This study reports the design, in silico evaluation of a series of 15 naphthyl-substituted sulfonamide derivatives targeting essential bacterial pathways. We designed 15 compounds to predict their binding affinities to a key bacterial enzyme particularly, Staph GyraseB. Compounds 6b and 6h exhibited the most favorable in-silico profiles, predicting significantly stronger binding interactions (docking scores of -7.1 kcal/mol and − 6.8 kcal/mol, respectively) compared to the standard drug Sulphamethoxazole (-5.5 kcal/mol). The stability of docked complex was determined by 100 ns molecular dynamic (MD) simulation approach. Based on these promising computational results, 6b and 6h were synthesized, characterized, and subsequently evaluated for their in vitro antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Disc diffusion assay demonstrated that both synthesized compounds displayed significant zones of inhibition. Compound 6b exhibited strong, dose-dependent activity against S. aureus, with the inhibition zone increasing from 11.3 mm at 10 µg/mL to 21.5 mm at 100 µg/mL. The Minimum Inhibitory Concentration (MIC) assays revealed that 6h (16.0 ± 2.02 µM) and 6b (13.15 ± 1.62 µM) possess an antibacterial activity, they were more potent than Sulphamethoxazole (17.61 ± 1.97 µM) against S. aureus. The superior in silico predicted binding affinities of 6b and 6h, coupled with their observed in vitro activity, highlight the potential of naphthyl-substituted sulfonamides as a promising scaffold for the development of new antibacterial agents, warranting further structural optimization and investigation against a broader spectrum of pathogens. Graphical abstract