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Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

Journal Article · · Organic and Biomolecular Chemistry
DOI:https://doi.org/10.1039/C5OB01930C· OSTI ID:1228099
 [1];  [1];  [1];  [1];  [1];  [2];  [2];  [2];  [3];  [4]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. School of Medicine (Japan)
  4. Kumamoto Univ. School of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States)
+ Show Author Affiliations
Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. Here, the majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.
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:
1228099
Journal Information:
Organic and Biomolecular Chemistry, Journal Name: Organic and Biomolecular Chemistry Journal Issue: 48 Vol. 13; ISSN OBCRAK; ISSN 1477-0520
Publisher:
Royal Society of ChemistryCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (3)

Lactols in Asymmetric Sequential Organo- and Gold-Catalysis: Synthesis of Densely Functionalized Epimeric Bicyclic O,O-Acetals journal October 2017
Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors journal June 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

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59 BASIC BIOLOGICAL SCIENCES
HIV-1 protease inhibitors
X-ray crystal structure
antiviral
backbone binding
darunavir
design
multidrug-resistant
synthesis