Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors.

α-Glucosidase is an important target in treating type 2 diabetes, and thus, the inhibition of this enzyme could delay sugar digestion and avoid postprandial hyperglycemia. Previous studies revealed that some pyrimidine and piperazine derivatives showed good affinity towards α-glucosidase. In continuing efforts toward the development of α-glucosidase inhibitor, a series of pyrimidinyl-piperazine carboxamide 6-22 containing chiral center have been synthesized. The inhibition activity was evaluated against α-glucosidase from Saccharomyces cerevisiae. All tested compounds exhibit excellent inhibition effects compared to acarbose (IC = 817.38 µM). Compounds bearing S-configurations at the chiral center displayed up to 5-fold more active than R-configurations. Among them, compounds 7c, 17c, 21c, and 22c were the top four compounds with IC values in a range of 0.4-1.5 µM. A kinetic study revealed that competitive inhibition as their mechanism of action. The results of the computational study indicated that hydrophobic interactions were the key factor in this activity. Moreover, molecular dynamics simulation showed that the 21c/α-glucosidase complex provided more stability by maintaining a consistent binding pose. MM-GBSA analysis revealed that the binding energy of 21c was approximately 11 kcal/mol lower than its counterpart, confirming the superiority of the S-configuration. The cytotoxicity test indicated that the top four compounds were not toxic to normal cells at the given IC value. Hence, these compounds are promising candidate as α-glucosidase inhibitors.