Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases

被引：33

作者：

Caridha, Diana ^{[1
]}

Kathcart, April K. ^{[1
]}

Jirage, Dayadevi ^{[1
]}

Waters, Norman C. ^{[1
]}

机构：

[1] Walter Reed Army Inst Res, Div Expt Therapeut, Silver Spring, MD 20910 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 13期

关键词：

Malaria; Plasmodium; Pfmrk; CDK inhibitor; CDK7; Kinase; Cancer; Cell cycle; PLASMODIUM-FALCIPARUM; SELECTIVE INHIBITORS; PFMRK; DESIGN; CDK; EXPRESSION; IDENTIFICATION; DISCOVERY; TARGETS; MODEL;

D O I：

10.1016/j.bmcl.2010.05.039

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3863 / 3867

页数：5

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