Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

Arun K. Ghosh, Heather L. Osswald, Kristof Glauninger, Johnson Agniswamy, Yuan Fang Wang, Hironori Hayashi, Manabu Aoki, Irene T. Weber, Hiroaki Mitsuya

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction.

Original languageEnglish
Pages (from-to)6826-6837
Number of pages12
JournalJournal of Medicinal Chemistry
Volume59
Issue number14
DOIs
Publication statusPublished - 2016 Jul 28
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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