Design, synthesis, and in silico evaluation of novel vanillic acid-thiosemicarbazide hybrids as dual antioxidant and α-glucosidase inhibitors

Herein, we report the rational design, synthesis, and comprehensive biological evaluation of a new class of vanillic acid–based thiosemicarbazide hybrids. Their antioxidant capacity (DPPH and ABTS radical scavenging assays) and α-glucosidase inhibitory activity were determined spectrophotometrically. Several derivatives demonstrated marked activity; in particular, compound 4a emerged as the most promising candidate, showing superior free-radical scavenging potency (IC50 = 3.28 μg/mL for DPPH and 0.13 μg/mL for ABTS), outperforming reference standards vitamin C (6.38 μg/mL) and Trolox (8.04 μg/mL). Computational analysis – including molecular docking and 100 ns molecular dynamics simulations – confirmed stable binding of compound 4a to the catalytic pocket of human peroxiredoxin 5 (PDB ID: 1HD2). Moreover, in silico ADMET prediction and drug-likeness assessment revealed that compound 4a fully complies with Lipinski’s Rule of Five and exhibits balanced absorption, distribution, metabolic stability, and low toxicity risk – hallmarks of viable lead compounds.