Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases
Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases
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DOI：
10.1016/j.bmcl.2010.05.039
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发表时间：
2010-07-01
影响因子：
2.7
通讯作者：
Waters, Norman C.
中科院分区：
文献类型：
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作者：
Caridha, Diana;Kathcart, April K.;Waters, Norman C.
细胞周期蛋白依赖性蛋白激酶（CDK）被用作几种真核病原体的药物靶标。在这项研究中，我们确定噻吩和苯磺酰胺类药物作为Pfmrk的有效抑制剂，Pfmrk是恶性疟原虫CDK，与人CDK7具有序列同源性。几种化合物显示出对CDK7的抑制剂选择性超过CDK1、CDK2和CDK6。这些化合物是针对抗药性寄生虫的适度抗疟剂，并且具有针对人细胞系测定的令人鼓舞的体外治疗指数。一个特定的化合物亚类，溴氢磺酰基乙酰胺，是具体的Pfmrk与IC 50值在亚微摩尔范围。这些化合物代表了报道的最有效的Pfmrk抑制剂，并为进一步表征和衍生作为潜在的抗疟剂提供了支持。爱思唯尔有限公司出版
Cyclin dependent protein kinases (CDKs) are pursued as drug targets for several eukaryotic pathogens. In this study, we identified thiophene and benzene sulfonamides as potent inhibitors of Pfmrk, a Plasmodium falciparum CDK with sequence homology to human CDK7. Several of the compounds demonstrated inhibitor selectivity for CDK7 over CDK1, CDK2, and CDK6. The compounds are moderate antimalarial agents against drug resistant parasites and possess encouraging in vitro therapeutic indices as determined against human cell lines. One particular sub-class of compounds, bromohydrosulfonylacetamides, was specific for Pfmrk with IC50 values in the sub-micromolar range. These compounds represent the most potent Pfmrk inhibitors reported and provide support for further characterization and derivation as potential antimalarial agents. Published by Elsevier Ltd.