Design, synthesis, structural characterization, and antioxidant potential of novel triazole- and oxadiazole-based hydrazide-hydrazone derivatives: spectroscopic, DFT, and molecular docking studies

A novel series of hydrazide-hydrazone derivatives incorporating 1,2,4-triazole and 1,2,4-oxadiazole scaffolds was synthesized through multistep condensation and cyclization reactions starting from 4-nitrobenzohydrazide. The structures of the synthesized compounds (MI-1 to MI-9) were confirmed by FTIR, ¹H NMR, and ¹³C NMR spectroscopy, complemented by elemental and mass analyses. Their antioxidant potential was assessed in vitro using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, where several derivatives demonstrated comparable or superior activity to ascorbic acid. To elucidate structure-activity relationships, density functional theory (DFT) calculations were performed to analyze optimized geometries, frontier molecular orbitals (HOMO-LUMO), and molecular electrostatic potential (MEP) surfaces. Furthermore, molecular docking studies against the Keap1-Nrf2 complex revealed favorable binding interactions for select compounds, highlighting their potential as antioxidant modulators through Nrf2 pathway activation. The combined spectroscopic, theoretical, and docking insights provide a comprehensive understanding of the structure-activity relationships of these novel heterocyclic derivatives and support their potential application as antioxidant therapeutic leads.