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

Authors

Daljit S. Matharu, University of Kansas
Daniel P. Flaherty, University of Kansas
Denise S. Simpson, Cedarville UniversityFollow
Chad E. Schroeder, University of Kansas
Donghoon Chung, University of Louisville
Dan Yan, Georgia State University
James W. Noah, Southern Research Institute
Colleen B. Jonsson, Southern Research Institute
E. Lucile White, Southern Research Institute
Jeffrey Aubé, University of Kansas
Richard K. Plemper, Georgia State University
William E. Severson, University of Louisville
Jennifer E. Golden, University of Kansas

Document Type

Article

Publication Date

12-26-2014

Journal Title

Journal of Medicinal Chemistry

ISSN

1520-4804

Volume

57

Issue

24

First Page

10314

Last Page

10328

DOI

http://dx.doi.org/10.1021/jm500902x

PubMed ID

25399509

PubMed Central® ID

PMC4281105

Abstract

A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC₅₀ = 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 (EC₅₀ = 300–500 nM, CC₅₀ > 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.

Keywords

Antiviral agents, quinazolinones, RNA replicase, respiratory syncytial viruses

Recommended Citation

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.; and Golden, Jennifer E., "Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity" (2014). Pharmaceutical Sciences Faculty Publications. 149.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/149