Synthesis of the new tri-amide derivatives as novel α-glucosidase inhibitors by Ugi four-component reaction

In this study, new tri-amides 5a-l have been synthesized via a one-pot four-component Ugi reaction between repaglinide, aniline derivatives, aldehyde derivatives, and cyclohexyl isocyanide in good yields. These compounds were evaluated against yeast α-glucosidase. Obtained in vitro α-glucosidase results demonstrated that all the synthesized compounds 5a-l were more potent than standard inhibitor acarbose. Among them, the most potent compounds were compounds 5j, 5k, and 5h. The kinetic analysis of the most potent compound 5j revealed that this compound is a competitive inhibitor for α-glucosidase (Ki = 24 µM). Furthermore, docking study of the most potent compounds was also performed in the α-glucosidase active site to find interaction modes and binding energies of these compounds.