Design and synthesis of N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide-based α-glucosidase inhibitors

This study investigates the design and synthesis of a series of novel selective α-glucosidase inhibitors based on N-(3-cyanothiophen-2-yl)-2-phenoxyacetamide framework, employing a bioisosterism strategy. Among the nineteen newly synthesized analogs, compound 4d9 demonstrated the highest α-glucosidase inhibitory potency (IC₅₀ = 2.11 μM) when compared to the established inhibitors Acarbose (IC₅₀ = 327.0 μM) and HXH8r (IC₅₀ = 15.32 μM), while exhibiting a remarkable 17.48-fold selectivity for α-glucosidase over α-amylase. Kinetic studies revealed that compound 4d9 acts as a non-competitive inhibitor, and its binding interactions were further investigated using molecular docking analysis. Additionally, compound 4d9 showed noncytotoxic effects on human normal hepatocyte (LO2) cells and demonstrated improved metabolic stability in rat plasma. These findings position compound 4d9 as a promising candidate for the development of therapeutics targeting type 2 diabetes.