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

Journal Article · · Journal of Medicinal Chemistry
 [1];  [1];  [1];  [2];  [2];  [3];  [4];  [2];  [5]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. Graduate School of Medical Sciences (Japan); National Center for Global Health and Medicine, Tokyo (Japan)
  4. Kumamoto Univ. Graduate School of Medical Sciences (Japan); National Inst. of Health (NIH), Bethesda, MD (United States); Kumamoto Health Science Univ. (Japan)
  5. Kumamoto Univ. Graduate School of Medical Sciences (Japan); National Center for Global Health and Medicine, Tokyo (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
+ Show Author Affiliations
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. Lastly, 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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1314251
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 14 Vol. 59; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV-1 protease inhibitors
X-ray crystal structure
adamantane
antiviral
backbone binding
darunavir
inhibitors
ligands
multidrug-resistant
noncovalent interactions
peptide isostere
peptides and proteins
reaction products
synthesis