Design and synthesis of azole derivatives of echinocystic acid as α-glucosidase inhibitors with hypoglycemic activity

Diabetes mellitus necessitates strict control of postprandial hyperglycemia via α-glucosidase inhibitors. In this study, novel azole derivatives of Echinocystic acid (EA), a natural pentacyclic triterpenoid, were synthesized through molecular hybridization to enhance hypoglycemic potential. Compound A4 exhibited superior α-glucosidase inhibition (IC₅₀ = 2.72 μM) than that of EA (IC₅₀ = 59.91 μM), and acarbose (IC₅₀ = 342.0 μM). Kinetic analysis revealed mixed-type inhibition (Ki = 15.31 μM, Kis = 10.23 μM), suggesting ternary complex formation. Analysis by spectroscopic studies confirmed A4 altered the enzyme's microenvironment and secondary structure. The combination of molecular docking and molecular dynamics simulations further elucidated the interaction between A4 and α-glucosidase. A4 enhanced binding stability through π-cation and π-π stacking interactions, with low RMSD values indicating structural stability. In vivo studies showed that A4 has an excellent safety profile, with no organ damage observed at a single dose of 0.5 g/kg. In a sucrose loading test in normal mice, A4 demonstrated glucose control comparable to that of acarbose at the same dose. Diabetic mice treated with A4 exhibited reduced fasting blood glucose, improved glucose tolerance, lipid normalization, and antioxidant effects, underscoring its therapeutic promise.

Azole derivatives; Echinocystic acid; Hypoglycemic activity; α-Glucosidase inhibition.