Synthesis and biological evaluation of novel oleanolic acid analogues as potential α-glucosidase inhibitors

• Published in: European journal of medicinal chemistry 2019-02, Vol.164, p.706-716
• Main Authors: Zhong, Ying-Ying, Chen, Hui-Sheng, Wu, Pan-Pan, Zhang, Bing-Jie, Yang, Yang, Zhu, Qiu-Yan, Zhang, Chun-Guo, Zhao, Su-Qing
• Format: Article
• Language: English
• Subjects: Hypoglycemic; Molecular docking; Oleanolic acid analogues; Synthesis; α-glucosidase inhibition
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.12.046

Considerable interest has been attracted in oleanolic acid and its analogues because of their hypoglycemic activity. In this study, a series of novel oleanolic acid analogues against α-glucosidase were synthesized and their biological activities were evaluated in vitro and in vivo. In vitro α-glucosidase inhibition activity results indicated that most of the designed analogues exhibited prominent inhibition activities, especially compounds 10, 15, 16 and 26 which with the IC50 values of 0.33 ± 0.01, 0.98 ± 0.06, 0.69 ± 0.01 and 0.72 ± 0.21 μM, respectively. Enzyme kinetic studies on the most potent compounds reveled that derivatives 10, 15, 16 and 26 were noncompetitive inhibitors. Moreover, the docking studies were carried out to prove that the four compounds could interact with the hydrophobic region of the active pocket and form hydrogen bonds to enhance the binding affinity of them with the α-glucosidase. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the active compounds (10, 15, 16 and 26) against normal 3T3 cell line. Furthermore, the in vivo actual pharmacological potential studies on derivatives 10, 15, 16 and 26 showed that the hypoglycemic effects of them were comparable to that of positive control, acarbose. [Display omitted] •A series of novel noncytotoxic oleanolic acid analogues were designed and synthesized as potential α-glucosidase inhibitors.•Compounds 10, 15, 16 and 26 were more potent in vitro than acarbose and OA.•Compounds 10, 15, 16 and 26 had comparable hypoglycemic effect to acarbose in vivo.•Kinetic studies demonstrated that compounds 10, 15, 16 and 26 were noncompetitive α-glucosidase inhibitors.•Docking study proved the four compounds could bind with the active site by hydrogen bonding and hydrophobic interactions.