Design and Synthesis of Sulfonium Derivatives: A Novel Class of α‑Glucosidase Inhibitors with Potent In Vivo Antihyperglycemic Activities

We report the first attempt of double-spot structural
modification
on a side-chain moiety of sulfonium-type α-glucosidase inhibitors
isolated from genus Salacia. A series of sulfonium
salts with benzylidene acetal linkage at the C3′ and C5′
positions were designed and synthesized. In vitro enzyme inhibition
evaluation showed that compounds with a strong electron-withdrawing
group attached at the ortho position on the phenyl
ring present stronger inhibitory activities. Notably, the most potent
inhibitor 21b (1.0 mpk) can exhibit excellent hypoglycemic
effects in mice, which can still compete with those of acarbose (20.0
mpk). Molecular docking of 21b demonstrated that besides
conventional interacting patterns, the newly introduced benzylidene
acetal moiety plays an important role in anchoring the whole molecule
in a concave pocket of the enzyme. The successful identification of 21b as a lead compound for new drug discovery may provide
a means for structure modification and diversification of the distinguished
sulfonium-type α-glucosidase inhibitors.