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

<i>Diabetes mellitus</i> 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 <b>8</b> and <b>10</b> showed the highest dual inhibition: compound <b>8</b> with IC₅₀ = 30.21 ± 0.16 μM (α-amylase) and 38.06 ± 0.80 μM (α-glucosidase); compound <b>10</b> 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 <b>7</b>) and 69.25 μM (compound <b>9</b>), 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 <b>8</b> and <b>10</b> with both enzymes' active sites. These findings highlight hydrazone scaffolds as potent and safe candidates for further antidiabetic drug development.