Antimalarial activity of new acridinone derivatives
Antimalarial activity of new acridinone derivatives
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DOI：
10.1016/j.biopha.2011.04.001
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发表时间：
2011-06-01
影响因子：
7.5
通讯作者：
Rojas, Lazara
中科院分区：
文献类型：
--
作者：
Fernandez-Calienes, Ayme;Pellon, Rolando;Rojas, Lazara
疟疾是世界公共卫生的主要威胁之一。对当前抗疟药物的耐药性导致人们寻找新的抗疟化合物。最近已证明吖啶酮衍生物具有对抗疟疾寄生虫的活性。我们将注意力集中在合成新的吖啶酮衍生物上，其中一些具有高抗病毒和杀锥虫活性。在这项研究中，评估了 10-烯基-、10-(3-甲基-2-丁烯基)-和 10-(1,2-丙二烯基)-9(10H)-吖啶酮的新衍生物对恶性疟原虫的抗疟活性。为了评估选择性，同时评估了针对人 MRC-5 细胞的细胞毒性。使用分光光度测定法测定对β-血红素形成的抑制。从酵母和牛心脏细胞中分离线粒体 bc(1) 复合物以测试吖啶酮抑制活性。这项研究鉴定出三种对恶性疟原虫具有亚微摩尔功效且对人类细胞系没有细胞毒性作用的化合物。一种化合物 IIa（1-氟-10-(3-甲基-2-丁烯基)-9(10H)-吖啶酮）可被列为抗疟药物开发的热门药物，其 IC50 小于 0.2 μg/mL，SI 大于 100。在分子测试中，我们的化合物没有获得相关的抑制活性。吖啶酮类抗疟作用的机制仍不清楚。 (C) 2011 Elsevier Masson SAS。版权所有。
Malaria is one of the major threats concerning world public health. Resistance to the current antimalarial drugs has led to searches for new antimalarial compounds. Acridinone derivatives have recently demonstrated to be active against malaria parasite. We focused our attention on synthesized new acridinone derivatives, some of them resulting with high antiviral and trypanocidal activity. In this study new derivatives of 10-alyl-, 10-(3-methyl-2-butenyl)- and 10-(1,2-propadienyl)-9(10H)-acridinone were evaluated for their antimalarial activity against Plasmodium falciparum. To assess the selectivity, cytotoxicity was assessed in parallel against human MRC-5 cells. Inhibition of beta-hematin formation was determined using a spectrophotometric assay. Mitochondrial bc(1) complexes were isolated from yeast and bovine heart cells to test acridinone inhibitory activity. This study resulted in the identification of three compounds with submicromolar efficacy against P. falciparum and without cytotoxic effects on human cellular line. One compound, IIa (1-fluoro-10-(3-methyl-2-butenyl)-9(10H)-acridinone), can be classified as hit for antimalarial drug development exhibiting IC50 less than 0.2 mu g/mL with SI greater than 100. In molecular tests, no relevant inhibitory activity was obtained for our compounds. The mechanism of acridinones antimalarial action remains unclear. (C) 2011 Elsevier Masson SAS. All rights reserved.