1,2,3-Triazole-based betulinic acid derivatives as α-glucosidase inhibitors: Synthesis and in vitro and in vivo biological evaluation

A series of 1, 2, 3-triazole-based betulinic acid derivatives d1 - d31 were synthesized as alpha-glucosidase inhibitors with hypoglycemic activity. All the derivatives exhibited excellent inhibition against alpha-glucosidase, and compound d23 was the most active (IC 50 = 2.83 +/- 0.19 mu M). Inhibition kinetics showed that compound d23 was a mixed-type inhibitor for alpha-glucosidase. Spectroscopic studies based on 3D fluorescence and circular dichroism spectra suggested that compound d23 exerted its inhibitory activity by changing the conformation of alpha-glucosidase. Molecular docking revealed that compound d23 was well nested into the active pocket of alpha-glucosidase through hydrogen-bonding and hydrophobic interactions. In vivo experiments showed that compound d23 could not only reduce the level of fasting blood glucose, but also improve glucose tolerance and dyslipidemia. The present findings strongly suggest that compound d23 is exploitable as a leading compound for the development of alpha-glucosidase inhibitors in the treatment of type 2 diabetes.