Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity
Journal of Medicinal Chemistry
PubMed Central® ID
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.
Antiviral agents, quinazolinones, RNA replicase, respiratory syncytial viruses
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.