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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

Abstract

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.

Authors:
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)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Inst. of Health
OSTI Identifier:
1482242
Grant/Contract Number:  
GM53386; GM62920
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
European Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 160; Journal Issue: C; Journal ID: ISSN 0223-5234
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; HIV-1 protease inhibitors; P2 ligand; drug resistance; design and synthesis; X-ray crystal structure

Citation Formats

Ghosh, Arun K., Jadhav, Ravindra D., Simpson, Hannah, Kovela, Satish, Osswald, Heather, Agniswamy, Johnson, Wang, Yuan-Fang, Hattori, Shin-ichiro, Weber, Irene T., and Mitsuya, Hiroaki. Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands. United States: N. p., 2018. Web. doi:10.1016/j.ejmech.2018.09.046.
Ghosh, Arun K., Jadhav, Ravindra D., Simpson, Hannah, Kovela, Satish, Osswald, Heather, Agniswamy, Johnson, Wang, Yuan-Fang, Hattori, Shin-ichiro, Weber, Irene T., & Mitsuya, Hiroaki. Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands. United States. doi:10.1016/j.ejmech.2018.09.046.
Ghosh, Arun K., Jadhav, Ravindra D., Simpson, Hannah, Kovela, Satish, Osswald, Heather, Agniswamy, Johnson, Wang, Yuan-Fang, Hattori, Shin-ichiro, Weber, Irene T., and Mitsuya, Hiroaki. Tue . "Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands". United States. doi:10.1016/j.ejmech.2018.09.046. https://www.osti.gov/servlets/purl/1482242.
@article{osti_1482242,
title = {Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands},
author = {Ghosh, Arun K. and Jadhav, Ravindra D. and Simpson, Hannah and Kovela, Satish and Osswald, Heather and Agniswamy, Johnson and Wang, Yuan-Fang and Hattori, Shin-ichiro and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {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.},
doi = {10.1016/j.ejmech.2018.09.046},
journal = {European Journal of Medicinal Chemistry},
issn = {0223-5234},
number = C,
volume = 160,
place = {United States},
year = {2018},
month = {9}
}

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Cited by: 1 work
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