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Title: Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

Journal Article · · European Journal of Medicinal Chemistry
ORCiD logo [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [2];  [4]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. National Center for Global Health & Medicine Research Inst., Tokyo (Japan)
  4. National Center for Global Health & Medicine Research Inst., Tokyo (Japan); Kumamoto University Graduate School of Medical and Pharmaceutical Sciences (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
+ Show Author Affiliations

We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health; USDOE Office of Science (SC)
OSTI ID:
1482242
Journal Information:
European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Journal Issue: C Vol. 160; ISSN 0223-5234
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV-1 protease inhibitors
P2 ligand
X-ray crystal structure
design and synthesis
drug resistance