Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents.

Journal Article (Journal Article)

In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC(50) = 0.09 microM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N'-[N-[3beta-hydroxy-lup-20(29)-en-28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3beta-O-(3',3'-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC(50) values of 0.007 and 0.006 microM, respectively. These results are slightly better than that of bevirimat (2, 3',3'-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.

Full Text

Duke Authors

Cited Authors

  • Qian, K; Yu, D; Chen, C-H; Huang, L; Morris-Natschke, SL; Nitz, TJ; Salzwedel, K; Reddick, M; Allaway, GP; Lee, K-H

Published Date

  • May 28, 2009

Published In

Volume / Issue

  • 52 / 10

Start / End Page

  • 3248 - 3258

PubMed ID

  • 19388685

Pubmed Central ID

  • PMC2736638

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm900136j


  • eng

Conference Location

  • United States