Structure–activity relationships of 3-O-β-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors

•A series of pentacyclic triterpenes have been designed and synthesized.•These compounds as H5N1 entry inhibitors exhibited the potent inhibitory activity.•Intensive SARs studies were conducted.•Introduction of a disubstituted amide structure at the 17-COOH can improve the SI.•Alteration of the C-3 configuration of ursolic acid improves the selective index.

A series of methyl ursolate 3-O-β-chacotrioside analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 3 previously discovered by us. Detailed structure–activity relationships (SARs) studies on the aglycone of compound 3 indicated that both the type of pentacyclic triterpene and the subtle modification of ursolic acid as an aglycon had key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of ursolic acid or alteration of the C-3 configuration of ursolic acid from 3β-to 3α-forms was helpful to significantly improve the selective index while keeping their antiviral activities.

Graphical abstractA series of pentacyclic triterpen were designed and synthesized in a practical way based on compound 3. Most compounds exhibited potent the inhibitory activity against the entry of H5N1 influenza virus.Figure optionsDownload full-size imageDownload as PowerPoint slide