Molecular docking, normal mode analysis and quantum chemical investigations of selected isoxazole-diphenylamine hybrids as potential antioxidants

Oxidative stress and related diseases caused by excessive amounts of free radicals can be prevented through the identification and development of antioxidants that safeguard biological systems against the radical-induced damage. Isoxazoles are biologically active chemical compounds with a broad range of activities, including antioxidant activity. This study employed the application of Density Functional Theory (DFT), molecular docking, Normal Mode Analysis (NMA) and pharmacokinetics profiling to investigate a systematic research on isoxazole-diphenylamine hybrids. DFT calculations confirmed the least energy band gap (4.4029 eV) in BIPB, indicating improved reactivity that was justified by the positive thermochemical properties and Fukui indices that characterized active atomic centers of reactive sites. The steric repulsion, van der Waals forces, as well as hydrogen-bond interactions were observed through Non-Covalent Interaction (NCI) analysis, which correlated with the Quantum Theory of Atoms in Molecules (QTAIM) results. Molecular docking against PDB: 1N3U and 3NRZ revealed that BIPB showed the best affinities of binding (-9.7 and -7.6 kcal/mol) compared to MIPB (-9.0 and -7.4 kcal/mol) and the reference antioxidant-Ascorbic acid (ASCA) (-5.5 and -5.7 kcal/mol) respectively. NMA further confirmed that BIPB–protein complexes exhibited lower eigenvalues compared to MIPB, which corresponded to biologically relevant conformations. ADMET predictions indicated that the compounds conformed to the rule of five proposed by Lipinski, but MIPB demonstrated potential carcinogenicity. BIPB emerged as the most promising isoxazole-based antioxidant due to the combination of high electronic reactivity, excellent protein binding, structural stability, as well as favorable drug-likeness, thus providing a strong theoretical background for further experimental validation.