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:	Ghosh AK; Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States., R Nyalapatla P; Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States., Kovela S; Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States., Rao KV; Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States., Brindisi M; Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States., Osswald HL; Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States., Amano M; Departments of Infectious Diseases and Hematology , Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556 , Japan.; Department of Medical Technology , Kumamoto Health Science University , Kumamoto 861-5598 , Japan., Aoki M; Departments of Infectious Diseases and Hematology , Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556 , Japan.; Department of Medical Technology , Kumamoto Health Science University , Kumamoto 861-5598 , Japan.; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch , National Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , United States., Agniswamy J; Molecular Basis of Disease, Department of Biology , Georgia State University , Atlanta , Georgia 30303 , United States., Wang YF; Molecular Basis of Disease, Department of Biology , Georgia State University , Atlanta , Georgia 30303 , United States., Weber IT; Molecular Basis of Disease, Department of Biology , Georgia State University , Atlanta , Georgia 30303 , United States., Mitsuya H; Departments of Infectious Diseases and Hematology , Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556 , Japan.; Department of Refractory Viral Infection , National Center for Global Health and Medicine Research Institute , Tokyo 162-8655 , Japan.; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch , National Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 May 24; Vol. 61 (10), pp. 4561-4577. Date of Electronic Publication: 2018 May 15.
DOI:	10.1021/acs.jmedchem.8b00298
Abstrakt:	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:	MEDLINE
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