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Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants

Journal Article · · Journal of Medicinal Chemistry
 [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [4];  [5];  [5];  [4];  [6]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); Kumamoto Health Science Univ. (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
  3. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
  4. Georgia State Univ., Atlanta, GA (United States)
  5. National Inst. of Health (NIH), Bethesda, MD (United States)
  6. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); National Center for Global Health and Medicine Research Inst., Tokyo (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
+ Show Author Affiliations
Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Furthermore, 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:
Intramural Research Program of the Center for Cancer Research; National Cancer Inst.; National Inst. of Health
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1368286
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 10 Vol. 60; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (12)

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening journal May 2019
Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors journal June 2018
Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen journal January 2019
A Structural View on Medicinal Chemistry Strategies against Drug Resistance journal January 2019
Gold(I)‐Catalyzed Cycloisomerization of 3‐Alkoxyl‐1,6‐diynes: A Facile Access to Bicyclo[2.2.1]hept‐5‐en‐2‐ones journal March 2020
Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants journal March 2018
Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies journal October 2019
Asymmetric Diels–Alder reaction of 3-(acyloxy)acryloyl oxazolidinones: optically active synthesis of a high-affinity ligand for potent HIV-1 protease inhibitors journal January 2019
Ligand-controlled palladium catalysis enables switch between mono- and di-arylation of primary aromatic amines with 2-halobenzothiazoles journal January 2020
Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified journal March 2018
Novel Protease Inhibitors Containing C-5-Modified bis -Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2′ Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance journal May 2019
Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified text January 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Antimicrobial agents
Inhibitors
Ligands
Noncovalent interactions
Peptides and proteins