Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X-ray Structural Analysis
| Autor: | Satish Kovela, Heather L. Osswald, Manabu Aoki, Arun K. Ghosh, Masayuki Amano, Kanury V. S. Rao, Johnson Agniswamy, Yuan-Fang Wang, Irene T. Weber, Hiroaki Mitsuya, Prasanth R. Nyalapatla, Margherita Brindisi |
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| Přispěvatelé: | Ghosh, A. K., Nyalapatla, R. P., Kovela, S., Rao, K. V., Brindisi, M., Osswald, H. L., Amano, M., Aoki, M., Agniswamy, J., Wang, Y. -F., Weber, I. T., Mitsuya, H. |
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Stereochemistry medicine.medical_treatment Substituent Ligand Stereoisomerism Crystallography X-Ray Ligands Ring (chemistry) Article Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound HIV Protease HIV-1 protease Models Catalytic Domain Drug Discovery medicine Humans Structure–activity relationship HIV Protease Inhibitor Crystallography Protease Molecular Structure biology Molecular Active site HIV Protease Inhibitors 030104 developmental biology HIV-1 Drug Design chemistry X-Ray biology.protein Molecular Medicine Human Model |
| Zdroj: | Journal of Medicinal Chemistry. 61:4561-4577 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands, are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors. |
| Databáze: | OpenAIRE |
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