Discovery and synthesis of novel beesioside I derivatives with potent anti-HIV activity

Abstract In this study, 12 known cycloartane triterpenoids ( 1 – 12 ) with four different skeletons isolated from the roots of Souliea vaginata were screened for the first time fo r in vitro anti-HIV activity using AZT as a standard. Among the compounds, beesioside I ( 1 ) showed the highest potency against HIV-1 NL4-3 with an EC 50 value of 2.32 μM (CC 50  > 40 μM). Preliminary structure-activity relationship (SAR) studies on 1 indicated that simple modification of its aglycone ( 13 ) could significantly influence the antiviral activity. Particularly, the introduction of an acyl group at the C-3 position of 13 led to significant improvement in both anti-HIV potency and selectivity index. Among all synthetically modified derivatives, compound 13g was the most potent compound with an EC 50 value of 0.025 μM and TI value greater than 800, comparable to those of 3- O -(3′,3′-dimethylsuccinyl)-betulinic acid (DSB, bevirimat). Other analogues exhibited strong to weak inhibition of HIV-1 replication in MT-4 cells. The length, carboxylic terminus, and C-3′ dimethyl substitution of the C-3 side chain substantially affected the anti-HIV activity. Finally, compound 13g was an effective agent against HIV with high potential for further investigation.