强效和选择性喹唑啉二酮的优化：呼吸道合胞病毒的抑制剂，可阻断RNA依赖性RNA聚合酶复合物的活性。
Optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity.
作者信息
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
机构信息
University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States.
出版信息
J Med Chem. 2014 Dec 26;57(24):10314-28. doi: 10.1021/jm500902x. Epub 2014 Dec 4.
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.
发现了一种喹唑啉二酮衍生的筛选命中物2，它对呼吸道合胞病毒具有细胞抗病毒活性（细胞病变效应半数有效浓度[CPE EC50]=2.1μM），在减少病毒后代方面具有中等效力（10μM时为4.2对数），且细胞毒性较小（选择性指数，SI约为24）。骨架优化产生了具有改善的效力和选择性特征的类似物。最值得注意的是化合物15和19（EC50=300 - 500 nM，CC50>50μM，SI>100），它们显著降低了病毒滴度（>400,000倍），并且有几种类似物被证明可阻断呼吸道合胞病毒的RNA依赖性RNA聚合酶复合物的活性。
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