Design, Synthesis, In Vitro, and In Silico Assessment of Fluoroquinolone‐Sulfonamide Hybrids as Promising Antibacterial Agents

C NMR, mass spectrometry, and HPLC. Ciprofloxacin (CPX)-based derivatives 5 and 6, bearing 4-nitrobenzenesulfonyl and 3-cyanobenzenesulfonyl moieties, demonstrated broad-spectrum activity against E. coli, S. aureus, and S. typhimurium. Compound 5 showed enhanced activity against S. typhimurium (MIC = 0.5 µg/mL), representing 30-fold improvement over CPX, and notable efficacy against E. coli (MIC = 2.0 µg/mL). Compound 6 demonstrated consistent potency (MIC = 1.0 µg/mL) across all tested strains, achieving 30-fold improvement against S. aureus and 15-fold enhancement against S. typhimurium. Structure-activity relationship (SAR) studies revealed that electron-withdrawing groups (EWGs) significantly enhanced potency, while electron-donating groups (EDGs) reduced activity. Molecular docking showed enhanced binding affinities toward relevant bacterial targets: E. coli (PDB ID: 1T7D), S. aureus (PDB ID: 5TW8), and S. typhimurium (PDB ID: 2XF4). ADMET predictions suggested acceptable pharmacokinetic and toxicity profiles. These findings establish EWG-substituted arylsulfonyl fluoroquinolones, especially compounds 5 and 6, as promising antibacterial candidates for further development.