Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation
| Autor: | Kristof Glauninger, Hironori Hayashi, Hiroaki Mitsuya, Arun K. Ghosh, Heather L. Osswald, Irene T. Weber, Johnson Agniswamy, Manabu Aoki, Yuan-Fang Wang |
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| Rok vydání: | 2016 |
| Předmět: |
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 |
| Zdroj: | Journal of medicinal chemistry. 59(14) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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