This study designs and synthesizes a series of sulfonium, selenonium, and ammonium salts featuring benzylidene acetal-modified side chains with 3′R stereochemistry. As potent α-glucosidase inhibitors. In vitro α-glucosidase inhibition assays identified 20b, 20l, and 21b as potent candidates with high safety profiles in normal cell lines. In vivo hypoglycemic activity evaluation, kinetic studies and molecular docking studies were performed on the most potent inhibitor 20b.

A series of sulfonium, selenonium, and ammonium salts featuring diverse benzylidene acetal side chain substituents are designed and synthesized. In contrast to the previous work, this study emphasized stereochemical inversion at the 3′-position and bioisosteric replacements at the sulfonium cationic center. In vitro α-glucosidase inhibition assays identified 20b, 20l, and 21b as potent inhibitors. In vivo, 20b (15.0 mg kg⁻¹) reduced postprandial blood glucose levels in sucrose-loaded mice by 40.6% (15 min), 49.5% (30 min), and 43.6% (60 min), surpassing acarbose (20.0 mg kg^{− 1}). Molecular docking of 20b with the N-terminal subunit of Maltase-Glucoamylase (ntMGAM) revealed an identical binding mode, where 3′-stereoinversion induced π– π stacking between the benzylidene acetal phenyl ring and Phe450 and electrostatic interactions between the ortho-nitro group and Asp203. Cytotoxicity assessments confirmed the favorable safety profile of selected compounds in normal cell lines. Enzyme kinetic studies demonstrated fully competitive inhibition of α-glucosidase by these sulfonium salts.