Synthesis, in vitro enzyme inhibitory and antioxidant activities of novel S -Alkylated indole-1,2,4-triazole acyl hydrazones targeting type 2 diabetes

Managing postprandial hyperglycemia and oxidative stress remains a major hurdle in type 2 diabetes treatment. To tackle this dual challenge, we synthesized a novel series of S-alkylated indole-1,2,4-triazole acyl hydrazones, evaluating their antidiabetic and antioxidant capacities. Synthesis involved cyclizing thiosemicarbazide intermediates, followed by S-alkylation and condensation. Target structures were confirmed using FT-IR,1H/13C-NMR spectroscopy, LC-MS, and elemental analysis. Enzyme assays revealed striking activity differences depending on the terminal benzylidene substitutions. The p-bromo-substituted compound (4d) stood out as a potent α-glucosidase inhibitor, achieving 42.49% inhibition at 50 µM and significantly outperforming acarbose (27.50%). Meanwhile, the p-methoxy derivative (4c) was the most effective α-amylase inhibitor (IC50=17.33 µM). While final hybrids (4a-e) exhibited limited antioxidant effects, parent triazole-thione (2) and hydrazide (3) intermediates retained notable DPPH scavenging and reducing activities, respectively. SAR analysis indicated that bulky, lipophilic para-halogens on the benzylidene ring maximize α-glucosidase inhibition. Molecular docking against yeast isomaltase and human pancreatic α-amylase mirrored experimental data, pointing to E/Z geometric isomerism as a defining factor in target recognition. Docking showed that 4d locks into α-glucosidase active site through strong, configuration-dependent halogen bonds in both isomeric forms, whereas Z-configuration of 4c provides the exact spatial alignment for α-amylase pocket. Ultimately, compound 4d emerges as a strong, synthetically accessible lead for targeted antidiabetics.