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Optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity.

ABSTRACT: A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC50 = 2.1 ?M), moderate efficacy in reducing viral progeny (4.2 log at 10 ?M), 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 ?M, 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.

SUBMITTER: Matharu DS

PROVIDER: S-EPMC4281105 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity.

Matharu Daljit S DS Flaherty Daniel P DP Simpson Denise S DS Schroeder Chad E CE Chung Donghoon D Yan Dan D Noah James W JW Jonsson Colleen B CB White E Lucile EL Aubé Jeffrey J Plemper Richard K RK Severson William E WE Golden Jennifer E JE

Journal of medicinal chemistry 20141204 24

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 ...[more]

PMID: 25399509

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