Structure-activity relationships of 3-O-β-chacotriosyl oleanic acid derivatives as entry inhibitors for highly pathogenic H5N1 influenza virus

摘要

Graphical abstract Display Omitted Highlights ? A series of oleanane-type triterpenes were designed and synthesized. ? These compounds as H5N1 entry inhibitors exhibited strong inhibitory activity. ? Intensive SARs studies were conducted. ? Introduction of an oxo group to position 11 at OA can enhance the SI. ? Alteration of the C-3 configuration of OA can improve the selective index. Abstract Highly pathogenic H5N1 virus (H5N1) entry is a key target for the development of novel anti-influenza agents with new mechanisms of action. In our continuing efforts to identify novel potential anti-H5N1 entry inhibitors, a series of 3- O -β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on two small molecule inhibitors 1 and 2 previously discovered by us. The anti-H5N1 entry activities were determined based on HA/HIV and VSVG/HIV entry assays. Compound 15 displayed the most promising anti-H5N1 entry activities with average IC 50 values of 4.05 μM and good selective index (22.9). Detailed structure-activity relationships (SARs) studies suggested that either the introduction of an additional oxo group to position 11 at OA or alteration of the C-3 configuration of OA from 3β- to 3α-forms can significantly enhance the selective index while maintaining their antiviral activities in vitro . Molecular simulation analysis confirmed that the compounds exert their inhibitory activity through binding tightly to hemagglutinin (HA2) protein near the fusion peptide and prevent virus entry. ]]>