Anti-AIDS Agents 81. Design Synthesis and Structure-Activity Relationship Study of Betulinic Acid and Moronic Acid Derivatives as Potent HIV Maturation Inhibitors

摘要

In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, >1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl- betulinic acid (MSB) analogs were also designed to better understand the contribution of the C-3′ dimethyl group of bevirimat (>2), the first-in-class HIV maturation inhibitor, which is currently in phase IIb clinical trials. In addition, another triterpene skeleton, moronic acid (MA, >3) was also employed to study the influence of the backbone and the C-3 modification towards the anti-HIV activity of this compound class. This study enabled us to better understand the structure-activity relationships (SAR) of triterpene-derived anti-HIV agents, and led to the design and synthesis of compound >12 (EC50: 0.0006 μM), which displayed slightly better activity than >2 as a HIV-1 maturation inhibitor.