Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed To Have Multiple Interactions with Heme
Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed To Have Multiple Interactions with Heme
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与三胺连接的两种芳烃的有效抗疟活性，旨在与血红素具有多种相互作用
DOI：
10.1021/acsmedchemlett.8b00222
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发表时间：
2018
影响因子：
4.2
通讯作者：
Haruto Ishikawa and Tsunehiko Higuchi
中科院分区：
文献类型：
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作者：
Yosuke Sakata;Kosuke Yabunaka;Yuko Kobayashi;Hirohisa Omiya;Naoki Umezawa;Hye- Sook Kim;Yusuke Wataya;Yoshimi Tomita;Yosuke Hisamatsu;Nobuki Kato;Hirokazu Yagi;Tadashi Satoh;Koichi Kato;Haruto Ishikawa and Tsunehiko Higuchi
基于设计对血红素表现出高亲和力的化合物将阻断疟原虫色素形成（疟原虫色素解毒的关键过程）的想法，我们合成了一系列在三胺的末端氨基上具有两个π-共轭部分的化合物。这些化合物在体外对氯喹敏感和氯喹耐药的恶性疟原虫均表现出中度至高度的抗疟活性。在aP. berghei感染的小鼠模型，3a和12显示出有效的抗疟活性，与青蒿琥酯相比，以及抗疟作用的持续时间延长。我们发现，对氯化血红素降解和抗疟活性的保护活性之间有很好的相关性。化合物8和3a强烈抑制血红素解毒蛋白催化的疟原虫色素形成。
Based on the idea that compounds designed to exhibit high affinity for heme would block hemozoin formation, a critical heme-detoxification process for malarial parasites, we synthesized a series of compounds with two π-conjugated moieties at terminal amino groups of triamine. These compounds exhibited moderate to high antimalarial activitiesin vitrotoward both chloroquine-sensitive and chloroquine-resistantPlasmodium falciparum. In aP. berghei-infected mouse model,3aand12ashowed potent antimalarial activities compared to artesunate, as well as a prolonged duration of antimalarial effect. We found a good correlation between protective activity against hemin degradation and antimalarial activity. Compounds8band3astrongly inhibited hemozoin formation catalyzed by heme detoxification protein.