Acetophenone-Substituted 5-(Methylamino)benzotriazole Mannich Bases: Synthesis, Molecular Modeling, and Antioxidant Potential

The condensation of 5-amino-1H-benzotriazole with substituted acetophenones and formaldehyde in the presence of an acid catalyst under microwave irradiation to produce 3-[(1H-benzotriazol-5-yl)amino]-1-phenylpropan-1-one derivatives. The structure of the synthesized compounds was confirmed by IR, 1H and 13C NMR, and mass spectra, and their antioxidant activity was evaluated by different assay procedures. Compounds 6a, 6c, and 6d at concentrations of 100 and 200 μg/mL showed higher activity in hydrogen peroxide scavenging by the replacement titration method. Compounds 6c–6f and 6h exhibited potency in total antioxidant capacity by the phosphomolybdenum method, and 6a–6e displayed higher activity than the standard in nitric oxide radical scavenging assay at 100 and 200 μg/mL concentrations. Molecular docking of the compounds with three receptors, nitric oxide synthase, sphingomyelinase-2, and xanthine oxidase, was performed to identify and confirm the best ligand–protein interactions. Among the examined compounds, 6a and 6e showed a good binding affinity against all three receptors and potent radical scavenging activity surpassing that of ascorbic acid. Molecular dynamics studies showed that compound 6e formed the most stable complex at the binding pocket of sphingomyelinase-2.