Design, Synthesis, In Vitro, and In Silico Enzymatic Evaluations of New Chrysin Sulfonohydrazide Derivatives as Potent α‑Glucosidase Inhibitors

  • ACS Omega. 2026 Jul 14;11(29):43921-43930. doi: 10.1021/acsomega.6c03656.
Toyin Florence Ayandokun  1 ,  Dung Thi Kim Le  2  3 ,  Warinthorn Chavasiri  1
Affiliations
  • 1. Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • 2. Laboratory of Biophysics, Institute for Advanced Study in Technology, Ton Duc Thang University, Ho Chi Minh City 72915, Vietnam.
  • 3. Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 72915, Vietnam.
PMID: 42540182 DOI: 10.1021/acsomega.6c03656
Abstract

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.

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