Elucidation of the pharmacophore of echinocystic acid, a new lead for blocking HCV entry

• Published in: European journal of medicinal chemistry 2013-06, Vol.64, p.160-168
• Main Authors: Wang, Han, Wang, Qi, Xiao, Su-Long, Yu, Fei, Ye, Min, Zheng, Yong-Xiang, Zhao, Chuan-Ke, Sun, Di-An, Zhang, Li-He, Zhou, De-Min
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Echinocystic acid; HCV entry inhibitor; Hepacivirus - drug effects; Microbial Sensitivity Tests; Microbial transformation; Molecular Conformation; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - chemistry; Oleanolic Acid - metabolism; Oleanolic Acid - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.03.041

To elucidate the pharmacophore of echinocystic acid (EA), an oleanane-type triterpene displaying substantial inhibitory activity on HCV entry, two microbial strains, Rhizopus chinensis CICC 3043 and Alternaria alternata AS 3.4578, were utilized to modify the chemical structure of EA. Eight new metabolites with regio- and stereo-selective introduction of hydroxyl and lactone groups at various inert carbon positions were obtained. The anti-HCV entry activity of the metabolites 2–13, along with their parental compound EA and other analogs 14–15, were evaluated. Most of the metabolites showed no improvement but detrimental effect on potency except compound 5 and 6, which showed similar and even a litter higher anti-HCV entry activity than that of EA. The results demonstrated that ring A, B, C and the left side of ring E of EA are highly conserved, while ring D and the right side of ring E of EA are flexible. Introduction of a hydroxyl group at C-16 enhanced the triterpene potency. Further analysis indicated that the hemolytic effect of EA disappeared upon such modifications. [Display omitted] •Triterpene natural products are proposed as a new class of compounds for blocking HCV entry.•The structure diversity of echinocystic acid was expanded via biotransformation.•The conserved sites and modifiable sites within the triterpene lead were elucidated.•The hemolytic effect of echinocystic acid was depleted upon biotransformation.