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Title: Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands

Journal Article · · Bioorganic and Medicinal Chemistry Letters
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  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. of Medicine (Japan)
  4. Kumamoto Univ. of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine, Tokyo (Japan)
+ Show Author Affiliations

We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2–P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2–P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11 Å resolution. Lastly, this structure revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health
Grant/Contract Number:
W-31-109-Eng-38; GM53386; GM62920
OSTI ID:
1224016
Alternate ID(s):
OSTI ID: 1250394
Journal Information:
Bioorganic and Medicinal Chemistry Letters, Vol. 25, Issue 21; ISSN 0960-894X
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 21 works
Citation information provided by
Web of Science

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Cited By (6)

Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents journal November 2019
A fission yeast cell-based system for multidrug resistant HIV-1 proteases journal January 2017
Synthesis and Biological Evaluation of New Multifunctional Oxazolone Scaffolds Incorporating Phenyl Benzoate Moiety: Synthesis and Biological Evaluation of New Multifunctional Oxazolone Scaffolds Incorporating Phenyl Benzoate Moiety journal March 2018
Development of methodologies for the regioselective synthesis of four series of regioisomer isoxazoles from β-enamino diketones journal January 2018
Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents text January 2019
Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents text January 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV-1 protease
inhibitors
design
synthesis
antiviral
isophthalamide