Discovery of Novel C‑glycosyl Pyranose-Based Sulfonium and Selenonium Salts Targeting α‑Glucosidase with Potent Antihyperglycemic Activity

α-Glucosidase inhibitors mitigate postprandial
hyperglycemia
by delaying carbohydrate hydrolysis. Guided by the principle of bioisosterism,
we transformed an acid-labile benzylidene acetal sulfonium scaffold
into acid-stable C-glycosyl pyranose–based sulfonium and selenonium
salts. The lead, 38f, inhibited rat intestinal maltase
and sucrase with IC50 values of 0.10 and 0.08 μM,
respectively, outperforming acarbose and voglibose, and showed excellent
stability in simulated gastric fluid and intestinal fluid. In vivo, 38f delivered robust, dose-efficient glucose lowering: at
1–3 mg/kg, it markedly suppressed postprandial excursions in
normal ICR mice and reduced fasting glucose in STZ-diabetic mice (3
mg/kg 32.8% vs acarbose 50 mg/kg 24.3%). Across OGTT/ITT and maltose/sucrose
tolerance tests, 38f improved glycemic end points, liver
glycogen, and HbA1c. Kinetic analyses support competitive inhibition
of α-glucosidase. A 14-day subacute study (≤500 mg/kg)
indicated an acceptable safety profile without hepatic or renal toxicity.
These acid-resistant C-glycosyl pyranose cationic glycomimetics merit
further development as antidiabetic agents.