Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum
Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum
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DOI：
10.1016/s0006-2952(01)00644-x
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发表时间：
2001-08-01
影响因子：
5.8
通讯作者：
Havlik, I
中科院分区：
文献类型：
--
作者：
Harmse, L;van Zyl, R;Havlik, I
恶性疟原虫耐药性的产生和迅速蔓延，使新型化疗药物的开发成为一项紧迫的任务。导致脑型疟疾的原生寄生虫细胞周期蛋白依赖性激酶（CDKs）是调节真核细胞周期所必需的，并且已经在恶性疟原虫中鉴定了该家族的几种酶。近年来，已经合成了许多嘌呤衍生激酶抑制剂，其中一些显示出对CDK的选择性活性。本报告描述了一项研究，其中各种嘌呤衍生物的体外抗疟活性进行了筛选。体外培养抗氯喹的恶性疟原虫株（FCR-3）的红细胞无性期，用[H-3]次黄嘌呤掺入法测定不同嘌呤对疟原虫增殖的影响。我们的研究结果显示恶性疟原虫对不同嘌呤的敏感性存在相当大的差异，并且与它们对纯化的海星CDK 1/细胞周期蛋白B活性的影响基本无关，后者一直是用于鉴定CDK特异性抑制剂的标准测定法。对CDK 1/细胞周期蛋白B活性具有中等至较差活性的两个嘌呤亚家族显示出对恶性疟原虫的亚微摩尔活性。结构-活性分析表明，某些结构特征与抗恶性疟原虫的活性增加相关。这些特征可用于合成对恶性疟原虫具有更高活性和特异性的化合物。(C)2001 Elsevier Science Inc. All rights reserved.
The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum. the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [H-3]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum. (C) 2001 Elsevier Science Inc. All rights reserved.