Design, synthesis, and bio-evaluation of novel triterpenoid derivatives as anti-HIV-1 compounds

Two betulinic acid derivatives, RPR103611 ( 2 ) and IC9564 ( 3 ) were previously reported to be potent HIV-1 entry inhibitors. In this current study, a SAR study of the triterpenoid moiety of 2 and 3 has been performed and an oleanolic acid derivative ( 4) was identified as a novel HIV-1 entry inhibitor. In addition, the combination of 4 with several-type of HIV-1 neutralizing antibodies provided significant synergistic effects. The synthetic utility of the C=C double bond in the C-ring of 4 was also demonstrated to develop the 12-keto-type oleanolic acid derivative ( 5 ) as a potent anti-HIV compound. This simple transformation led to a significantly increased anti-HIV activity and a reduced cytotoxicity of the compound.