Synthesis and Biological Evaluation of Substituted Pyrazole-Fused Oleanolic Acid Derivatives as Novel Selective α-Glucosidase Inhibitors.

ABSTRACT

A series of novel substituted pyrazole-fused oleanolic acid derivative were synthesized and evaluated as selective α-glucosidase inhibitors. Among these analogs, compounds 4a-4f exhibited more potent inhibitory activities compared with their methyl ester derivatives, and standard drugs acarbose and miglitol as well. Besides, all these analogs exhibited good selectivity towards α-glucosidase over α-amylase. Analog 4d showed potent inhibitory activity against α-glucosidase (IC50 =2.64±0.13 µM), and greater selectivity towards α-glucosidase than α-amylase by ∼33-fold. Inhibition kinetics showed that compound 4d was a non-competitive α-glucosidase inhibitor, which was consistent with the result of its simulation molecular docking. Moreover, the in vitro cytotoxicity of compounds 4a-4f towards hepatic LO2 and HepG2 cells was tested.