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.