Chloroquine analogs as antimalarial candidates with potent in vitro and in vivo activity.
Chloroquine analogs as antimalarial candidates with potent in vitro and in vivo activity.
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DOI：
10.1016/j.ijpddr.2018.10.002
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Krettli AU
中科院分区：
文献类型：
--
作者：
Aguiar ACC;Murce E;Cortopassi WA;Pimentel AS;Almeida MMFS;Barros DCS;Guedes JS;Meneghetti MR;Krettli AU
尽管最近在世界范围内努力消除疟疾，但这种寄生虫病仍然被认为是一个主要的公共卫生问题，2016年共有2.16亿例疟疾病例和44.5万例死亡。基于青蒿素的联合疗法在世界大部分地区仍然有效，但东南亚最近出现的耐药性病例促使人们寻求新的方法来治疗恶性疟原虫引起的疟疾。在这项工作中，我们提出了氯喹类似物，表现出对敏感和氯喹抗性恶性疟原虫血液寄生虫的高活性，也对伯氏疟原虫感染的小鼠有活性。在测试的化合物中，DAQ，一种具有更线性侧链的氯喹类似物，显示出在体外和体内最具活性，具有低细胞毒性，因此可以作为开发更有效的氯喹类似物以帮助根除疟疾的基础。N-（4-（二甲基氨基）丁-2-烯基）-7-氯-喹啉-4-胺（DAQ）的合成：DAQ是一种具有更直链侧链的氯喹类似物，对敏感的和氯喹抗性的恶性疟原虫血液寄生虫表现出高活性，并且对伯氏疟原虫感染的小鼠也有活性。对世卫组织推荐的疟疾疗法的抗药性正在出现。具有修饰侧链的氯喹类似物可克服恶性疟原虫抗性。DAQ是一种具有更线性侧链的CQ类似物，是最有前途的测试化合物。DAQ可以作为一种先导化合物，用于设计更有效的抗疟药物。
In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and were also active against P. berghei infected mice. Among the compounds tested, DAQ, a chloroquine analog with a more linear side chain, was shown to be the most active in vitro and in vivo, with low cytotoxicity, and therefore may serve as the basis for the development of more effective chloroquine analogs to aid malaria eradication. Synthesis of N-(4-(dimethylamino)but-2-enyl)-7-chloro-quinolin-4-amine (DAQ): DAQ, a chloroquine analog with a more linear side chain, exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and was also active against P. berghei infected mice. Resistance to recommended malaria therapies by WHO is emerging. Chloroquine analogs with modified side chains may overcome P. falciparum resistance. DAQ, a CQ-analog with a more linear side chain, is the most promising tested compound. DAQ may serve as a lead compound for the design of more effective antimalarials.
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影响因子：
5.1
作者：
Kondaparla, Srinivasarao;Soni, Awakash;Katti, S. B.
通讯作者：
Katti, S. B.
影响因子：
7.3
作者：
Kaschula, CH;Egan, TJ;Monti, D
通讯作者：
Monti, D
影响因子：
1.5
作者：
Menting, JG;Tilley, L;Foley, M
通讯作者：
Foley, M
影响因子：
1.5
作者：
Gligorijevic, Bojana;Purdy, Kyle;Roepe, Paul D.
通讯作者：
Roepe, Paul D.
影响因子：
3
作者：
Hassinen, T;Peräkylä, M
通讯作者：
Peräkylä, M