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

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.