Sulfathiazole scaffold remodeling into benzothiazole-thiazole Schiff bases: Antibacterial activity against Staphylococcus aureus, structure-activity relationships, and integrated DFT, docking and molecular dynamics studies.

The growing challenge of antimicrobial resistance highlights the need for rational modification of established antibacterial scaffolds. In this study, sulfathiazole (St) was structurally remodeled into a series of benzothiazole-thiazole Schiff-base derivatives (B1-B10) to enhance its antibacterial activity. The synthesized compounds were evaluated by antibacterial assays, SAR, DFT, MEP, molecular docking, ADMET prediction, and 100-ns molecular dynamics simulations. Within the narrow-spectrum screening panel, the derivatives showed preferential activity against the tested clinical Staphylococcus aureus isolate, while no detectable inhibition was observed against the tested clinical Escherichia coli isolate in the disk-diffusion assay. B2, B4, and B8 exhibited the lowest operational MIC of 0.25 mg mL-1, whereas parent St did not reach the MIC endpoint within the tested range. B8 emerged as the lead compound, producing 99.97% growth inhibition and the largest inhibition zone of 11.89 ± 0.12 mm. DFT analysis further identified B8 as the most electronically responsive derivative, with the smallest HOMO-LUMO gap (0.08979 Hartree), highest softness, and highest electrophilicity. Molecular docking revealed improved binding affinities for the Schiff-base derivatives relative to St, with B7 showing the best docking score (-8.2913 kcal mol-1), while B8 formed multiple interactions with Ser82, Ser238, and His271. The single 100-ns MD trajectory showed that the modeled B8-MurB complex maintained a relatively stable association over the simulated period. Overall, sulfathiazole scaffold remodeling through benzothiazole cyclization and Schiff-base diversification generated derivatives with enhanced antibacterial activity against the tested clinical S. aureus isolate, identifying B8 as a promising lead for further optimization toward S. aureus-targeted antibacterial agents.