Design and synthesis of potent substrate-based inhibitors of the Trypanosoma cruzi dihydroorotate dehydrogenase
Design and synthesis of potent substrate-based inhibitors of the Trypanosoma cruzi dihydroorotate dehydrogenase
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DOI：
10.1016/j.bmc.2017.01.009
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发表时间：
2017-02-15
影响因子：
3.5
通讯作者：
Inoue, Masayuki
中科院分区：
文献类型：
--
作者：
Inaoka, Daniel Ken;Lida, Maiko;Inoue, Masayuki
查加斯病是由寄生性原虫克氏锥虫引起的，是拉丁美洲心脏病的主要原因。克鲁兹毛滴虫二氢罗酸脱氢酶(DHODH)催化甲酸的产生，是克氏毛滴虫生存所必需的，因此被认为是防治恰加斯病的潜在药物靶点。在这里，我们报道了75个基于orotate结构的化合物的设计和合成。一项全面的构效关系(SAR)研究揭示了两个5-取代的orotate类似物(5U和5V)，它们的NPP值为几十纳摩尔水平，选择性是人DHODH的30,000多倍。这里提供的信息对于寻找治疗恰加斯病的下一代药物线索将是无价的。(C)2017爱思唯尔有限公司。保留所有权利。
Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, is the leading cause of heart disease in Latin America. T. cruzi dihydroorotate dehydrogenase (DHODH), which catalyzes the production of orotate, was demonstrated to be essential for T. cruzi survival, and thus has been considered as a potential drug target to combat Chagas disease. Here we report the design and synthesis of 75 compounds based on the orotate structure. A comprehensive structure-activity relationship (SAR) study revealed two 5-substituted orotate analogues (5u and 5v) that exhibit nPP values of several ten nanomolar level and a selectivity of more than 30,000-fold over human DHODH. The information presented here will be invaluable in the search for next-generation drug leads for Chagas disease. (C) 2017 Elsevier Ltd. All rights reserved.