N‐(1H‐Indazolyl) Aryl Sulfonamide Hybrids as Potential Dihydropteroate Synthase Inhibitors: In Vitro Antibacterial Activity Against Escherichia coli and Staphylococcus aureus and Computational Modeling

Abstract

Antimicrobial resistance (AMR) has severely compromised the clinical utility of classical sulfonamide antibiotics, primarily owing to the emergence of resistance‐associated dihydropteroate synthase variants. In this study, sixteen N‐(1H‐indazolyl) aryl sulfonamide hybrids were evaluated as potential DHPS inhibitors against Escherichia coli and Staphylococcus aureus using disk diffusion, broth microdilution (MIC80), and minimum bactericidal concentration (MBC) assays. Active compounds were characterized by in silico ADME and toxicity profiling, with molecular docking performed against wild‐type DHPS and the sulfonamide‐resistant Sul1 variant. Antibacterial activity was species‐dependent: compound 4 showed the strongest activity against E. coli (MIC = 32 µg/mL), while compounds 11 and 16 were most potent against S. aureus (MIC = 32 µg/mL), outperforming sulfathiazole and sulfisoxazole. All hybrids showed superior docking affinities to sulfamethoxazole (SMX), with compound 11 showing the highest affinity for wild‐type DHPS (−7.79 kcal/mol); compound 4 retained favorable binding against Sul1 (−6.83 kcal/mol), suggesting potential resistance resilience. Structure–activity analysis showed antibacterial efficacy is governed by aryl sulfonyl electronic effects, steric balance at the C7 indazole position, and physicochemical properties affecting Gram‐negative membrane permeability. These findings support indazole–sulfonamide hybrids as promising scaffolds that may retain predicted binding complementarity toward the Sul1‐resistant DHPS variant, warranting validation against resistant isolates and purified DHPS enzymes.