Novel Hydroxychalcone-Based Dual Inhibitors of Aldose Reductase and α-Glucosidase as Potential Therapeutic Agents against Diabetes Mellitus and Its Complications.

We designed a novel series of bifunctional inhibitors of α-glucosidase and aldose reductase (ALR2) based on the structure of hydroxychalcone. The two enzymes relate to blood glucose level and anomalously elevated polyol pathway of glucose metabolism under hyperglycemia, respectively. Most compounds in the series exhibited a potent inhibitory activity for both enzymes, and a significant antioxidant property was shown. Further in vivo studies of 11j and 14d using streptozotocin (STZ)-induced diabetic rats as a model found that 11j achieved not only good antihyperglycemic and glucose tolerance effect in a dose-dependent manner (p < 0.01) but also showed effective inhibition of polyol pathway. 14d significantly suppressed the maltose-induced postprandial glucose elevation. Additionally, they effectively improved lipid metabolisms and restored an antioxidant ability. Therefore, the two compounds may be promising agents for the prevention and treatment of diabetic complications.