Pharmaceutical Sciences Faculty Publications

Title

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

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