Novel Vanillic Acid Derivatives Containing a Semicarbazide Moiety as Potential Antioxidant Inhibitors

Abstract In this study, a series of novel vanillic acid semicarbazide hybrids were successfully synthesized and structurally characterized via 1H, 13C NMR, and HRMS. The in vitro antioxidant potential of all target compounds was systematically assessed by DPPH and ABTS radical scavenging assays. Biological screening results demonstrated that compound 2-(4-hydroxy-3-methoxybenzoyl)-N-isopropylhydrazine-1-carboxamide exhibited in vitro outstanding radical scavenging potency with the half-maximal inhibitory concentration (IC50) values of 4.7 and 0.2 μg/mL toward DPPH and ABTS radicals, respectively, which were remarkably lower than those of vanillic acid, vitamin C and trolox. Meanwhile, molecular docking simulations further revealed that compound 2-(4-hydroxy-3-methoxybenzoyl)-N-isopropylhydrazine-1-carboxamide could form multiple stable interactions with the active pocket of human peroxiredoxin 5 (PDB entry: 4K7N), which rationally explained its potent antioxidant activity at the molecular level. Moreover, in silico ADMET and drug-likeness evaluations indicated that compound 2-(4-hydroxy-3-methoxybenzoyl)-N-isopropylhydrazine-1-carboxamide possessed favorable physicochemical profiles, acceptable oral bioavailability and negligible toxic risks, highlighting its great potential as a lead antioxidant candidate for further pharmaceutical development.