Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.
Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.
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DOI：
10.1021/acs.jmedchem.6b00275
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发表时间：
2016-06-09
影响因子：
7.3
通讯作者：
Rathod PK
中科院分区：
文献类型：
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作者：
Kokkonda S;Deng X;White KL;Coteron JM;Marco M;de Las Heras L;White J;El Mazouni F;Tomchick DR;Manjalanagara K;Rudra KR;Chen G;Morizzi J;Ryan E;Kaminsky W;Leroy D;Martínez-Martínez MS;Jimenez-Diaz MB;Bazaga SF;Angulo-Barturen I;Waterson D;Burrows JN;Matthews D;Charman SA;Phillips MA;Rathod PK
疟疾仍然是最具破坏性的全球传染病之一。嘧啶生物合成酶二氢乳清酸脱氢酶（DHODH）已被确定为新的疟疾药物靶点，基于三唑并嘧啶的DHODH抑制剂1（DSM265）正在临床开发中。我们试图鉴定对疟原虫 DHODH 具有更高效力的化合物，同时对动物 DHODH 显示出更高的选择性。在本文中，我们描述了一系列新型三唑并嘧啶，其中对-SF5-苯胺被取代的1,2,3,4-四氢-2-萘基或2-茚满基胺取代。这些化合物表现出很强的物种选择性，并鉴定了几种高效的四氢-2-萘基衍生物。具有卤素取代的化合物在啮齿动物口服给药后表现出持续的血浆水平，从而在恶性疟原虫 SCID 小鼠疟疾模型中发挥功效。这些数据表明，四氢-2-萘基衍生物有可能有效治疗疟疾，但由于代谢清除率高于 1，它们很可能需要成为多剂量方案的一部分。
Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.