Structural modification of 4'-aminochalcones as α-glucosidase inhibitors

Diabetes mellitus, one of the most predominant health problems worldwide, characterized by hyperglycemia, has attracted the attention of medicinal chemists. Although several therapeutic drugs have been developed and used clinically, diabetes continues to pose a growing threat to public health. One of the promising approaches for treating type 2 diabetes involves reducing the rate of carbohydrate hydrolysis by inhibiting the action of α-glucosidase. Over the years, chalcone analogues have been reported for their vast biological properties and as a promising antidiabetic agent. In this research, two series of 4'-aminochalcone derivatives were designed and synthesized as α-glucosidase inhibitors. Twenty-five alkylated 4'-aminochalcone (E2-E15, E22-E24, E25-E30, E33, E34) were synthesized via a one-pot reductive amination of 4'-aminochalcone and aldehyde derivatives, and thirteen sulfonamide chalcones (E48-E60) were synthesized by Claisen-Schmidt reaction. All the compounds were characterized by NMR technique, and the HRMS of novel derivatives were determined. The compounds were tested for α-glucosidase inhibitory activity. All the compounds exhibited excellent activities compared to the standard drug, acarbose. For the alkylated derivatives, four compounds exhibited very strong activity (IC50 0.05 - 0.01 µM), seven with strong activity (IC50 8.76 - 1.39 µM) and fourteen with weak activity. E24 and E29 with p-methoxy and m-hydroxy groups on the B ring showed the strongest inhibitory activity with IC50 of 0.05 and 1.39 µM, respectively, at 50 µM. For the sulfonamide chalcones, four showed excellent activity with IC50 values ranging from 0.04 - 0.09 µM, another four showed strong activity (IC50 1.04 to 3.20 µM), and the rest showed moderate activity at 10 µM. The Lineweaver-Burk plot for the enzymatic kinetics of E24, E29 and E56 showed an uncompetitive inhibition mechanism.