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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

Journal Article · · Journal of Medicinal Chemistry
 [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [4];  [4];  [5]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); Kumamoto Health Science Univ. (Japan)
  3. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); Kumamoto Health Science Univ. (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
  4. Georgia State Univ., Atlanta, GA (United States)
  5. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); National Center for Global Health and Medicine Research Institute, Tokyo (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
+ Show Author Affiliations
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. As a result, 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.
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:
1460842
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 10 Vol. 61; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
alcohols
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inhibitors
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