Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum.
Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum.
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DOI：
10.1021/acs.jmedchem.0c02022
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发表时间：
2021-03-11
影响因子：
7.3
通讯作者：
Phillips MA
中科院分区：
文献类型：
--
作者：
Lawong A;Gahalawat S;Okombo J;Striepen J;Yeo T;Mok S;Deni I;Bridgford JL;Niederstrasser H;Zhou A;Posner B;Wittlin S;Gamo FJ;Crespo B;Churchyard A;Baum J;Mittal N;Winzeler E;Laleu B;Palmer MJ;Charman SA;Fidock DA;Ready JM;Phillips MA
疟疾控制计划继续受到抗药性的威胁。为了鉴定新的抗疟药，我们进行了表型筛选，并鉴定了一种新的基于四唑的系列，该系列显示出快速杀灭动力学和相对较低的发展高水平耐药性的倾向。初步的结构活性关系（SAR）的建立，包括确定一个子系列的相关酰胺与抗疟原虫活性。分析寄生虫对抗疟药的耐药性使我们测试该系列是否具有与氯喹（CQ）相似的作用机制。用活性类似物处理同步化的恶性疟原虫寄生虫，揭示了一种细胞内抑制疟原虫色素（Hz）形成的模式，这让人想起CQ的作用。药物选择仅产生与多药耐药基因1（pfmdr1）扩增相关的适度耐药性。因此，我们已经确定了一种新的化学系列，其靶向历史上可药物化的血红素聚合途径，并且可以形成未来优化努力以开发新的疟疾治疗的基础。
Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure activity relationships (SAR) were established including identification of a sub-series of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized P. falciparum parasites with active analogs revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ’s action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway, and that can form the basis of future optimization efforts to develop a new malaria treatment.
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影响因子：
15.8
作者：
Delves M;Plouffe D;Scheurer C;Meister S;Wittlin S;Winzeler EA;Sinden RE;Leroy D
通讯作者：
Leroy D
影响因子：
4
作者：
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影响因子：
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DOI：
10.1016/j.ijpddr.2015.05.003
发表时间：
2015-12
影响因子：
4
作者：
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通讯作者：
Wright, David W.
影响因子：
16.6
作者：
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通讯作者：
Baum, Jake