Voglibose

Developing effective α-glucosidase inhibitors is critical for managing hyperglycemia in individuals with high-carbohydrate diets; however, current drugs exhibit limitations in both efficacy and tolerability. In the present study, 25 derivatives of neoponkoranol, an active sulfonium type α-glucosidase inhibitor identified from Genus Salacia were synthesized. These compounds containing a methyl-glycosyl furanose scaffold modified with various hydrophobic groups at the 5'-O-position, were characterized using HRMS and NMR spectroscopy. Biological evaluations demonstrated a selectively enhanced maltase inhibition profile while maintaining broad-spectrum activity. Most sulfonium salts exhibited potent inhibitory activity against maltase and sucrase with IC₅₀ values ranging from 0.14 to 2.21 μM; these potencies are comparable to or superior to those of the positive controls acarbose and voglibose. In addition, the designed derivatives also exhibited strong isomaltase inhibitory activities whereas acarbose was almost inactive against this enzyme. Compound LY-23 emerged as the most potent inhibitor with maltase IC₅₀ = 0.18 ± 0.03 μM, sucrase IC₅₀ = 0.14 ± 0.01 μM, and isomaltase IC₅₀ = 0.51 ± 0.06 μM. Mechanism studies characterized LY-23 as a competitive inhibitor. Molecular docking along with 3D fluorescence and CD spectral analyses indicated that LY-23 binds to α-glucosidase, inducing secondary structural and conformational changes in the enzyme. Furthermore, LY-23 showed no significant cytotoxicity in HEK293T and L02 cells. Remarkably, in vivo studies revealed that the oral administration of LY-23 (1.0 or 10.0 mg/kg) effectively reduced postprandial blood glucose levels in normal ICR mice following maltose or sucrose loading, with an efficacy comparable to that of voglibose (1.0 mg/kg) and acarbose (20.0 mg/kg), respectively. These findings highlight LY-23 as a promising candidate for the development of novel α-glucosidase inhibitors with antihyperglycemic properties.