Abstract: Herein, a novel S-glycoside derivatives were designed and synthesized using euparin as the aglycone. Employing a palladium-catalyzed strategy, 22 S-glycosides were efficiently synthesized under mild conditions with high chemoselectivity and stereoselectivity. Evaluation of the in vitro α-glucosidase inhibitory activities of these compounds showed that compounds 5a, 5d, and 7 exhibited potent inhibitory activity, with IC?? values of 2.7 μmol/L, 5.7 μmol/L, and 12.1 μmol/L, respectively. Molecular docking studies revealed that these active compounds bind to the active site of α-glucosidase through hydrogen bonds(with ASP382 and HIS326 residues) and π-π stacking interactions(with PHE144 residue), contributing to high binding affinity(docking score: -32.409 kJ/mol). This study provides a mild and efficient synthetic method for euparin-derived S-glycosides and identifies promising lead compounds for the development of novel anti-diabetic drugs.

Key words: Diabetes mellitus, Euparin, α-Glucosidase, S-Glycoside; Palladium catalysis