Benzylidenehydrazine Derivatives: Synthesis, Antidiabetic Evaluation, Antioxidation, Mode of Inhibition, DFT and Molecular Docking Studies.

Diabetes mellitus (DM) is a metabolic condition that is a profound health concern across the globe due to its contribution to the increased mortality rate. It affects millions of people around the world and is associated with severe complications among people diagnosed with it. Among the array of approaches used for the management of DM, inhibition of enzymes viz. α-amylase and α-glucosidase which are responsible for sugars hydrolysis is regarded as a feasible therapeutic protocol for the management of DM. Herein, we report the synthesis of benzylidenehydrazine derivatives as well as their evaluation as α-glucosidase and α-amylase inhibitors including their antioxidant testing. Generally, all the synthesized derivatives were more potent inhibitors of α-amylase than of α-glucosidase. Specifically, 2,4 fluoro substituted analogue 9 (IC =116.19 μM) emerged as the strongest α-amylase inhibitor with ~5-fold superior activity in comparison to the standard drug, acarbose (IC =600 μM). Compounds 18 (IC =240.59) and 19 (IC =198.32 μM) displayed the strongest NO scavenging activity compared to Trolox (IC =272.36 μM). In addition, the enzyme kinetic studies indicated that compound 9 acts as a non-competitive inhibitor of α-amylase. Finally, density functional theory and molecular docking studies for compound 9 were conducted to explore its structural and electronic properties as well as to determine protein-ligand interactions, respectively to decipher its observed activity. The obtained findings present promising possibilities for developing new drug candidates to control postprandial glucose levels in persons with diabetes.