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Title: 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. 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:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1409115
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorganic and Medicinal Chemistry Letters; Journal Volume: 27; Journal Issue: 21
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Ghosh, Arun K., Sean Fyvie, W., 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., Sean Fyvie, W., 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. doi:10.1016/j.bmcl.2017.09.003.
Ghosh, Arun K., Sean Fyvie, W., 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. doi:10.1016/j.bmcl.2017.09.003.
@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 Sean Fyvie, W. 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. 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 Nov 01 00:00:00 EDT 2017},
month = {Wed Nov 01 00:00:00 EDT 2017}
}