Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle
Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle
复制标题
DOI：
10.1021/acs.jmedchem.6b01265
复制
发表时间：
2016-11-10
影响因子：
7.3
通讯作者：
Chibale, Kelly
中科院分区：
文献类型：
--
作者：
Le Manach, Claire;Nchinda, Aloysius T.;Chibale, Kelly
水增溶基团的引入。在2-氨基吡嗪系列的5-苯基环上的发现导致鉴定出针对人类疟疾寄生虫恶性疟原虫的血液生命周期阶段的高效化合物。几种化合物在两种不同的疟疾小鼠模型（伯氏疟原虫感染的小鼠和恶性疟原虫感染的NOD-scid IL-2 R γ（无效）小鼠）中显示出高的体内功效。其中一个领跑者，化合物3，被鉴定为也具有良好的药代动力学和另外对肝脏和配子体寄生虫生命周期阶段非常有效的活性。
Introduction of water-solubilizing groups. on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2R gamma(null) mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.