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Molecular Design and Synthesis of Ivermectin Hybrids Targeting Hepatic and Erythrocytic Stages of Plasmodium Parasites.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-02-14 , DOI: 10.1021/acs.jmedchem.0c00033
Lovepreet Singh 1 , Diana Fontinha 2 , Denise Francisco 2 , Antonio M Mendes 2 , Miguel Prudêncio 2 , Kamaljit Singh 1
Affiliation  

Ivermectin is a powerful endectocide, which reduces the incidence of vector-borne diseases. Besides its strong insecticidal effect on mosquito vectors of the disease, ivermectin inhibits Plasmodium falciparum sporogonic and blood stage development and impairs Plasmodium berghei development inside hepatocytes, both in vitro and in vivo. Herein, we present the first report on structural modification of ivermectin to produce dual-action molecular hybrids with good structure-dependent in vitro activity against both the hepatic and erythrocytic stages of P. berghei and P. falciparum infection, suggesting inclusion of ivermectin antimalarial hybrids in malaria control strategies. The most active hybrid displayed over threefold and 10-fold higher in vitro activity than ivermectin against hepatic and blood stage infections, respectively. Although an overwhelming insecticidal effect against Anopheles stephensi mosquitoes in laboratory conditions was not noticed, in silico docking analysis supports allosteric binding to glutamate-gated chloride channels similar to ivermectin.

中文翻译:

靶向疟原虫寄生虫肝和红细胞阶段的伊维菌素杂种的分子设计和合成。

伊维菌素是一种强大的内杀菌剂,可减少媒介传播疾病的发生率。伊维菌素除了对这种疾病的蚊媒具有很强的杀虫作用外,还可以在体外和体内抑制恶性疟原虫的孢子形成和血液阶段发育,并削弱肝细胞中伯氏疟原虫的发育。本文中,我们首次报道了伊维菌素的结构修饰,以产生对伯氏疟原虫和恶性疟原虫感染的肝和红细胞阶段均具有良好的结构依赖性体外活性的双重作用分子杂合体,表明包括了伊维菌素抗疟杂种疟疾控制策略。与伊维菌素相比,活性最高的杂种对肝脏和血液阶段感染的体外活性分别高出三倍和十倍。
更新日期:2020-02-14
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