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, <b>38f</b>, 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, <b>38f</b> 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, <b>38f</b> 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.