New N‐ (Acyloxy) and N ‐(Benzyloxy)Amide Derivatives: Synthesis, Antibacterial Activity, and Molecular Docking Studies

ABSTRACT N‐ (Acyloxy) and N ‐(benzyloxy)amide derivatives were synthesized using aldoximes and carboxylic acids mediated by phenyl iodine(III) diacetate (PIDA) under mild reaction conditions in good to excellent isolated yields. The carboxylate group of hypervalent iodine (III) reagent attacks the nitrile oxide formed in situ, which is followed by intramolecular rearrangement to form the desired products. We have evaluated the synthesized compounds for antibacterial activity and found inhibitory potential against various Gram‐positive and Gram‐negative bacterial strains. Compound 4y was identified as the most promising with an MIC value of 1024 µg/mL against various bacterial strains. Again, compound 4y showed a significant synergistic effect with ampicillin against Staphylococcus aureus and Pseudomonas aeruginosa with fractional inhibitory concentration index (FICI) values of 0.37 and 0.15, respectively. In vitro, biofilm inhibition studies revealed compound 4y to be a moderate inhibitor of the biofilm formation phase (at ½MIC, 35% inhibition) of the bacterial lifecycle. Molecular docking studies showed potential binding modes with critical amino acid residues in human PelA protein. To better understand the molecular basis of a key biofilm‐associated protein, molecular docking and 100 ns simulation experiments were conducted.