Design, Synthesis, In Vitro, and In Silico Enzymatic Evaluations of New Chrysin Sulfonohydrazide Derivatives as...

Eleven new chrysin sulfonohydrazide derivatives were designed, synthesized, and screened for their in vitro α-glucosidase inhibitory activity. Their structures were unambiguously confirmed using NMR and mass spectrometry. All the synthesized compounds demonstrated significant inhibitory activity against the yeast α-glucosidase with IC₅₀ values ranging from 3.8 ± 0.4 to 9.6 ± 0.6 μM. Among them, compound 8 showed the strongest inhibitory activity, with an IC₅₀ value of 3.8 ± 0.4 μM, which was substantially more potent than the positive control, acarbose (IC₅₀ = 836.1 ± 47.2 μM). Enzyme kinetic studies revealed that compound 8 acts as a competitive inhibitor with a Ki value of 12.9 μM. To further investigate its binding mode, molecular docking and molecular dynamics simulations were performed. The docking results indicated that the enhanced α-glucosidase inhibitory activity was mainly attributed to π-π stacking interactions with Phe137 and hydrogen-bonding interactions involving Ser308, Pro309, Arg312, and Glu350. Molecular dynamics simulations further demonstrated that compound 8 forms stable interactions with key amino acid residues through hydrogen bonds and hydrophobic contacts, thereby contributing to its potent α-glucosidase inhibitory activity.