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 IC 50 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.