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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
- Source :
- Journal of medicinal chemistry. 59(14)
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
Models, Molecular
Stereochemistry
Adamantane
medicine.medical_treatment
Crystallography, X-Ray
Ligands
01 natural sciences
Article
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
HIV-1 protease
HIV Protease
Drug Discovery
medicine
Molecule
Structure–activity relationship
HIV Protease Inhibitor
Protease
biology
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Ligand
Chemistry
Enantioselective synthesis
HIV Protease Inhibitors
0104 chemical sciences
030104 developmental biology
Drug Design
biology.protein
Molecular Medicine
Hydrophobic and Hydrophilic Interactions
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 59
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....ee4b436c16cf601cba91ce4f477ac4fd