Open AccessProbing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation
Author(s) -
Arun K. Ghosh,
Heather L. Osswald,
Kristof Glauninger,
Johnson Agniswamy,
Yuan Fang Wang,
Hironori Hayashi,
Manabu Aoki,
Irene T. Weber,
Hiroaki Mitsuya
Publication year - 2016
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.6b00639
Subject(s) - chemistry , ligand (biochemistry) , stereochemistry , hiv 1 protease , protease inhibitor (pharmacology) , adamantane , protease , enzyme inhibitor , enantioselective synthesis , enzyme , human immunodeficiency virus (hiv) , receptor , biochemistry , organic chemistry , medicine , family medicine , antiretroviral therapy , viral load , catalysis
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.