Design, Synthesis and Molecular Docking-Based Evaluation of Piperazine-Linked Triazine Derivatives as Antioxidant Agents

Abstract

Oxidative stress is a key driver of the pathogenesis of numerous chronic inflammatory and metabolic diseases emphasizing the requirement for the development of potent and selective antioxidant therapeutics. In present study, a series of novel piperazine-linked 1,3,5-triazine derivatives (6a-h) was rationally designed, synthesised and evaluated for antioxidant activity using integrated computational and experimental approaches. Molecular docking studies were carried out against myeloperoxidase (MPO; PDB ID: 1DNU), a heme-containing enzyme involved in reactive oxygen species (ROS) generation, to examine ligand–protein interactions and binding affinities. The synthesized compounds exhibited binding energies ranging from -3.816 to -4.987 kcal/mol. Among them, compound 6f, bearing a para-fluorophenyl substituent, shows the highest binding affinity (-4.987 kcal/mol). The enhanced binding was attributed to the formation of two hydrogen bonds with ARG27 and LEU97 and exceeded the binding energy of the reference antioxidant, ascorbic acid (-4.690 kcal/mol). The antioxidant potential was assessed by the DPPH free radical scavenging assay. Compound 6f displayed the strongest activity with an IC₅₀ value of 14.15 ± 0.14 µM, which was comparable to that of ascorbic acid (IC₅₀ = 14.06 ± 0.18 µM). Structure-activity relationship analysis indicated that the electron-withdrawing substituents at the para-position of aryl ring, together with nitrogen-containing heteroaromatic moieties, improve both binding affinity and free radical scavenging activity. The results identify piperazine-linked 1,3,5-triazine derivatives as promising antioxidant scaffolds and provide a strong basis for future myeloperoxidase inhibition studies and in vivo pharmacological evaluation.