Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands
Abstract
Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. Lastly, these compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.
- Authors:
-
- Purdue Univ., West Lafayette, IN (United States)
- Georgia State Univ., Atlanta, GA (United States)
- Kumamoto Univ. of Medicine (Japan)
- Kumamoto Univ. of Medicine (Japan); National Inst. of Health (NIH), Bethesda, MD (United States); National Center for Global Health and Medicine, Tokyo (Japan)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Inst. of Health
- OSTI Identifier:
- 1409115
- Grant/Contract Number:
- GM53386; GM62920
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Bioorganic and Medicinal Chemistry Letters
- Additional Journal Information:
- Journal Volume: 27; Journal Issue: 21; Journal ID: ISSN 0960-894X
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; HIV protease; drug resistance; P1′-P2′ ligands; macrocyclic inhibitors; structure-based design
Citation Formats
Ghosh, Arun K., Fyvie, W. Sean, Brindisi, Margherita, Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands. United States: N. p., 2017.
Web. doi:10.1016/j.bmcl.2017.09.003.
Ghosh, Arun K., Fyvie, W. Sean, Brindisi, Margherita, Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., & Mitsuya, Hiroaki. Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands. United States. https://doi.org/10.1016/j.bmcl.2017.09.003
Ghosh, Arun K., Fyvie, W. Sean, Brindisi, Margherita, Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Wed .
"Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands". United States. https://doi.org/10.1016/j.bmcl.2017.09.003. https://www.osti.gov/servlets/purl/1409115.
@article{osti_1409115,
title = {Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands},
author = {Ghosh, Arun K. and Fyvie, W. Sean and Brindisi, Margherita and Steffey, Melinda and Agniswamy, Johnson and Wang, Yuan-Fang and Aoki, Manabu and Amano, Masayuki and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. Lastly, these compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.},
doi = {10.1016/j.bmcl.2017.09.003},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 21,
volume = 27,
place = {United States},
year = {Wed Sep 06 00:00:00 EDT 2017},
month = {Wed Sep 06 00:00:00 EDT 2017}
}
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