Green Synthesis, Antibacterial Activity, and Molecular Docking Study of γ‐Phosphonyloxime Derivatives

Abstract

Herein, we report an efficient, fast, and green approach to synthesize γ‐phosphonyloximes ( 2 ) via microwave‐assisted oximation of γ‐phosphonylketones under solvent‐free conditions. This method achieved high yields (up to 95%) in just 5 min. Subsequent O‐acetylation of these oximes yielded novel O ‐acetyloxime derivatives ( 3 ). Structural characterization of all the synthesized compounds was performed using FT‐IR, NMR ( 1 H, 3 1 P, and 1 3 C), mass spectrometry, and x‐ray crystallography (for  2a ), confirming their configuration as mixtures of  E / Z  isomers with predominant E‐forms. The antibacterial activity was evaluated against Gram‐positive (Staphylococcus aureus) and Gram‐negative (Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhimurium) strains. The O‐acetylated compounds ( 3 ) exhibited superior activity compared to their oxime precursors ( 2 ), with  3a  identified as the most potent agent (MIC = 20–40 µg/mL). Molecular docking studies against E. coli FabH enzyme revealed that  3a  binds deeper in the active site (binding energy: −5.5 kcal/mol) near the catalytic Cys 1 1 2 residue, while  2a  binds peripherally (−4.8 kcal/mol). This computational insight corroborates the enhanced antibacterial efficacy of  3a  and suggests FabH inhibition as a potential mechanism.