Glycerol‐Mediated, PIFA‐Promoted Synthesis of Novel Indoline‐2,3‐Dione‐Linked Isoxazole Scaffolds: Antibacterial Evaluation, Drug‐Likeness Prediction, and Molecular Dynamics Studies

Abstract

A novel, efficient, and environmentally benign protocol has been developed for the metal‐free synthesis of indoline‐2,3‐dione tied isoxazole scaffolds. The reaction proceeds smoothly under the promotion of [bis(trifluoroacetoxy)iodo]benzene (PIFA) utilizing glycerol as a recyclable reaction medium. All newly synthesized isoxazole derivatives were characterized and evaluated for their in vitro antibacterial efficacy against a panel of pathogenic bacterial strains, with several candidates displaying potent inhibitory profiles. To understand the underlying mechanism of action, in silico molecular docking simulations were performed against bacterial peptide deformylase (PDF), a critical enzyme for microbial growth. The top‐performing lead compounds exhibited high binding affinities and established crucial hydrogen bonding and hydrophobic interactions within the active pocket of the target enzyme. Furthermore, comprehensive 100 ns molecular dynamics (MD) simulations confirmed the structural stability and rigidity of the ligand‐protein complexes over time. Computational drug‐likeness predictions and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling further substantiated that these hybrids possess favorable pharmacokinetic parameters and excellent compliance with Lipinski's rule of five. Taken together, these findings highlight these novel isoxazole‐linked indoline‐2,3‐dione hybrids as promising lead candidates for the development of potent, next‐generation antibacterial agents.