Antibacterial Activity of α‐Sulfamidophosphonate Derivatives and Their In Silico Assessment as Dihydropteroate Synthase Binders

Abstract

In this study, we report the first antibacterial evaluation of a focused library of 12 previously synthesized α‐sulfamidophosphonate derivatives (4a–4l) against a panel of nine Gram‐positive and Gram‐negative strains, including ESBL‐ and carbapenemase‐producing Enterobacterales. The overall hit rate was modest, as most compounds were inactive at the highest tested concentration (MIC ≥ 256 µg/mL), indicating a narrow and strain‐selective profile. Nevertheless, selected derivatives showed noteworthy activity against individual isolates: 4 g inhibited Staphylococcus aureus ATCC29213 at 4 µg/mL, 4c inhibited KPC‐3‐producing Klebsiella pneumoniae at 2 µg/mL, and 4e and 4l inhibited VIM‐producing Escherichia coli at 4 µg/mL. Density functional theory (DFT) calculations were used to examine substituent‐dependent electronic features, whereas docking and 100 ns molecular dynamics (MD) simulations were employed to test whether the scaffold can adopt plausible binding modes in a dihydropteroate synthase (DHPS) model. Because no biochemical DHPS assay was performed, the computational results should be regarded as hypothesis‐generating rather than mechanistic proof. In silico ADMET predictions were used as an exploratory triage step and similarly await experimental validation. Overall, the present work identifies α‐sulfamidophosphonates as preliminary antibacterial hits for further optimization, while emphasizing the need for broader microbiology, cytotoxicity, bactericidal, and target‐validation studies.