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.