α-Glucosidase-IN-98 is a potent orally active α-glucosidase inhibitor with an IC₅₀ value of 18.1 μM. It reversibly binds to α-glucosidase through hydrogen bonding, electrostatic interactions, and hydrophobic interactions, inducing significant conformational changes in the enzyme's secondary structure. This compound can reduce postprandial blood glucose levels in mice with starch/sucrose loads and is applicable in research related to type 2 diabetes (T2DM).

α-glucosidase:18.1 μM

α-Glucosidase-IN-98 (compound 5c) demonstrates potent α-glucosidase inhibitory activity in the presence of polysaccharides (Acacia gum, Pectin), contrasting sharply with reduced efficacy in protein, fatty acid, or PEG environments. At concentrations of 0–40 μM, it reversibly inhibits α-glucosidase through non-covalent interactions, exhibiting a stronger binding affinity for the enzyme-substrate complex (K_i = 13.9 μM) than for the free enzyme (K_i = 42.2 μM). The binding involves hydrogen bonds (with Asp69, Asp352, His280), electrostatic interactions (with Asp215, Asp315), and hydrophobic interactions (with Val216), consistent with static quenching results. At concentrations of 0–46.4 μM, α-Glucosidase-IN-98 decreases the surface hydrophobicity of α-glucosidase by 29.4% and induces structural changes characterized by reduced α-helices and increased β-sheets, thereby enhancing rigidity and suggesting stabilization by occupying the enzyme's hydrophobic cavities.

Administered orally at doses of α-Glucosidase-IN-98 (10, 20, and 40 mg/kg), this compound reduces postprandial hyperglycemia in mice subjected to starch/sucrose loading in a dose-dependent manner.