Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity

[Image: see text] A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC(50) = 2.1 μM), moderate efficacy in reducing viral progeny (4.2 log at 10 μM), and marginal cytotoxic liability (selectivity index, SI ∼ 24). Scaff...

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Autores principales: Matharu, Daljit S., Flaherty, Daniel P., Simpson, Denise S., Schroeder, Chad E., Chung, Donghoon, Yan, Dan, Noah, James W., Jonsson, Colleen B., White, E. Lucile, Aubé, Jeffrey, Plemper, Richard K., Severson, William E., Golden, Jennifer E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281105/
https://www.ncbi.nlm.nih.gov/pubmed/25399509
http://dx.doi.org/10.1021/jm500902x
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author Matharu, Daljit S.
Flaherty, Daniel P.
Simpson, Denise S.
Schroeder, Chad E.
Chung, Donghoon
Yan, Dan
Noah, James W.
Jonsson, Colleen B.
White, E. Lucile
Aubé, Jeffrey
Plemper, Richard K.
Severson, William E.
Golden, Jennifer E.
author_facet Matharu, Daljit S.
Flaherty, Daniel P.
Simpson, Denise S.
Schroeder, Chad E.
Chung, Donghoon
Yan, Dan
Noah, James W.
Jonsson, Colleen B.
White, E. Lucile
Aubé, Jeffrey
Plemper, Richard K.
Severson, William E.
Golden, Jennifer E.
author_sort Matharu, Daljit S.
collection PubMed
description [Image: see text] A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC(50) = 2.1 μM), moderate efficacy in reducing viral progeny (4.2 log at 10 μM), and marginal cytotoxic liability (selectivity index, SI ∼ 24). Scaffold optimization delivered analogs with improved potency and selectivity profiles. Most notable were compounds 15 and 19 (EC(50) = 300–500 nM, CC(50) > 50 μM, SI > 100), which significantly reduced viral titer (>400,000-fold), and several analogs were shown to block the activity of the RNA-dependent RNA-polymerase complex of RSV.
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spelling pubmed-42811052015-11-15 Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity Matharu, Daljit S. Flaherty, Daniel P. Simpson, Denise S. Schroeder, Chad E. Chung, Donghoon Yan, Dan Noah, James W. Jonsson, Colleen B. White, E. Lucile Aubé, Jeffrey Plemper, Richard K. Severson, William E. Golden, Jennifer E. J Med Chem [Image: see text] A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC(50) = 2.1 μM), moderate efficacy in reducing viral progeny (4.2 log at 10 μM), and marginal cytotoxic liability (selectivity index, SI ∼ 24). Scaffold optimization delivered analogs with improved potency and selectivity profiles. Most notable were compounds 15 and 19 (EC(50) = 300–500 nM, CC(50) > 50 μM, SI > 100), which significantly reduced viral titer (>400,000-fold), and several analogs were shown to block the activity of the RNA-dependent RNA-polymerase complex of RSV. American Chemical Society 2014-11-15 2014-12-26 /pmc/articles/PMC4281105/ /pubmed/25399509 http://dx.doi.org/10.1021/jm500902x Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Matharu, Daljit S.
Flaherty, Daniel P.
Simpson, Denise S.
Schroeder, Chad E.
Chung, Donghoon
Yan, Dan
Noah, James W.
Jonsson, Colleen B.
White, E. Lucile
Aubé, Jeffrey
Plemper, Richard K.
Severson, William E.
Golden, Jennifer E.
Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity
title Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity
title_full Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity
title_fullStr Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity
title_full_unstemmed Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity
title_short Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity
title_sort optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block rna-dependent rna-polymerase complex activity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281105/
https://www.ncbi.nlm.nih.gov/pubmed/25399509
http://dx.doi.org/10.1021/jm500902x
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