Design, Synthesis, Antidiabetic Activity and In Silico Studies of New Hydrazone Derivatives Derived from Acetohexamide

Abstract

Diabetes mellitus affects over 500 million people globally and is expected to rise significantly in the coming decades. Existing antidiabetic drugs, including α-glucosidase and α-amylase inhibitors, often exhibit side effects and limited efficacy, prompting the search for safer alternatives. Hydrazone derivatives have shown promising antidiabetic activity due to their structural diversity and enzyme-targeting potential. In this study, 10 novel hydrazone compounds were synthesized and evaluated for their inhibitory effects against α-amylase and α-glucosidase. Compounds 8 and 10 showed the highest dual inhibition: compound 8 with IC₅₀ = 30.21 ± 0.16 μM (α-amylase) and 38.06 ± 0.80 μM (α-glucosidase); compound 10 with IC₅₀ = 34.49 ± 0.37 and 40.44 ± 0.23 μM, respectively. Cytotoxicity on HEK293 cells via MTT assay revealed IC₅₀ values of 61.04 μM (compound 7) and 69.25 μM (compound 9), while other compounds and acarbose were nontoxic up to 100 μM. In silico drug-likeness analysis showed that 80% of the compounds complied with Lipinski’s rules, with topological polar surface area (TPSA) values ranging between 63 and 112 Ų. Gastrointestinal absorption was high for 7 out of 10 compounds; none showed blood–brain barrier permeability. Molecular docking confirmed strong binding interactions of compounds 8 and 10 with both enzymes’ active sites. These findings highlight hydrazone scaffolds as potent and safe candidates for further antidiabetic drug development.