Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV)
in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds
T1-
T4 shown different extents of NO-releasing abilities and potent antioxidant abilities
in vivo. By screening in DPP-4, compound
T4 was recognized as a potent DPP-4 inhibitor with the IC
50 value of 0.060?μM. Docking study revealed compound
T4 has a favorable binding mode. Furthermore, compounds
T1-
T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation
in vitro. The overall results suggested that
T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound
T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.
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