Design, synthesis and biological evaluation of a 1,2,3-triazolyl-bearing betulinic acid derivatives as α-glucosidase inhibitors

In this study, a series of betulinic acid (BA) derivatives incorporating a 1,2,3-triazolyl unit, that is, compounds c1 - c21 and d1 - d21 were synthesized and evaluated for their inhibitory activity toward alpha-glucosidase. All the derivatives exhibited excellent inhibition against alpha-glucosidase, and compound d2 was the most active (IC50 = 0.89 +/- 0.025 mu M). Inhibition kinetics showed that compound d2 was a mixed-type inhibitor for alpha-glucosidase. The analysis of three-dimensional fluorescence and circular dichroism spectra suggested that compound d2 exerted its inhibitory activity by changing the conformation of alpha-glucosidase. Molecular docking revealed that compound d2 was well embedded into the active pocket of alpha-glucosidase through hydrogen-bonding and hydrophobic interactions. In vivo experiments showed that compound d2 not only reduced the level of fasting blood glucose, but also improved glucose tolerance and dyslipidemia. The present findings suggest that compound d2 has high potential as an alpha-glucosidase inhibitor for the treatment of type 2 diabetes.