Similar structure-activity relationships of quinoline derivatives for antiprion and antimalarial effects
Similar structure-activity relationships of quinoline derivatives for antiprion and antimalarial effects
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DOI：
10.1021/jm0602763
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发表时间：
2006-08-24
影响因子：
7.3
通讯作者：
Korth, Carsten
中科院分区：
文献类型：
--
作者：
Klingenstein, Ralf;Melnyk, Patricia;Korth, Carsten
朊病毒疾病总是致命的神经退行性疾病，其中的传染源由PrPSc组成，PrPSc是正常细胞朊病毒蛋白（PrPC）的一种致病性错误折叠亚型。到目前为止，还没有针对这些新型病原体的药理学选择。在这里，我们描述了一系列的聚喹啉和喹啉连接到大量的各种终端组的能力，治愈持续性朊病毒感染的细胞系（ScN 2a）的筛选。几种化合物在纳摩尔范围内显示出抗朊病毒活性。最具活性的分子，命名为42，具有50 nM的抗朊病毒活性的半数有效浓度（EC 50）。在喹啉衍生物的库中，我们能够确定几个结构-活性关系（SAR）。值得注意的是，抗朊病毒在ScN 2a细胞中的SAR与抗疟疾在疟疾细胞模型中的SAR相似，特别是对于磺胺喹啉衍生物，这表明抗朊病毒和抗疟疾物质的一些分子靶标重叠。
Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrPSc, a pathogenic misfolded isoform of the normal cellular prion protein ( PrPC). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.