Improved 2,4-diarylthiazole-based antiprion agents: switching the sense of the amide group at C5 leads to an increase in potency.
Improved 2,4-diarylthiazole-based antiprion agents: switching the sense of the amide group at C5 leads to an increase in potency.
复制标题
改进的 2,4-二芳基噻唑类抗朊病毒剂：改变 C5 酰胺基的意义可提高效力。
DOI：
10.1002/cmdc.201000217
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发表时间：
2010
期刊：
影响因子：
3.4
通讯作者：
Thompson MJ
中科院分区：
文献类型：
--
作者：
Thompson MJ
合成2，4-二芳基噻唑-5-羧酸的酰胺衍生物，并在朊病毒疾病的细胞系模型中测试其功效。因此，从筛选文库中鉴定出许多显示抗朊病毒活性的化合物，相对于先前已记录的相关2，4-二苯基-5-氨基噻唑的酰胺衍生物，其显示出改善的效力和结果的再现性。因此，“转换”噻唑C5上酰胺键的意义揭示了一系列更有希望的潜在朊病毒疾病治疗方法。此外，在文库合成过程中作为副产物分离的3，5-二芳基-1，2，4-噻二唑提供了少数具有抗朊病毒作用的额外实例，从而增加了新鉴定的活性化合物的集合。与细胞朊病毒蛋白（PrPC）结合的评价显示，最多只有弱亲和力，这表明新鉴定的抗朊病毒剂不通过与PrPC的直接相互作用介导其生物学效应。
Amide derivatives of 2,4‐diarylthiazole‐5‐carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease. A number of compounds demonstrating antiprion activity were thereby identified from the screening libraries, showing improved potency and reproducibility of results relative to amide derivatives of the related 2,4‐diphenyl‐5‐aminothiazole, which have been documented previously. Thus, 'switching' the sense of the amide bond at thiazole C5 revealed a more promising lead series of potential prion disease therapeutics. Furthermore, 3,5‐diaryl‐1,2,4‐thiadiazoles isolated as by‐products during library synthesis provided a handful of additional examples possessing an antiprion effect, thereby augmenting the set of newly identified active compounds. Evaluation of binding to cellular prion protein (PrPC) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrPC.