Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides
Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides
复制标题
DOI：
10.1021/acs.jmedchem.0c01755
复制
发表时间：
2021-04-01
影响因子：
7.3
通讯作者：
Auclair, Karine
中科院分区：
文献类型：
--
作者：
Guan, Jinming;Spry, Christina;Auclair, Karine
引起疟疾的疟原虫寄生虫正在对抗疟疾药物产生耐药性，这为新的抗疟原虫药物提供了动力。虽然泛酸酰胺显示出有效的抗疟原虫活性，但血液中存在的泛酰巯基乙胺酶/vanins的水解会迅速使其失活。本文报道了一个泛酸酰胺类似物的小型库的简易合成和生物活性，其中不稳定的酰胺基团被杂芳环取代。这些类似物中的几种显示出针对恶性疟原虫和/或诺氏疟原虫的纳摩尔抗疟原虫活性，并且在泛酰巯基乙胺酶存在下是稳定的。进一步表征了已知的三唑和新型异恶唑衍生物，发现其具有高选择性指数、中等或高Caco-2渗透性和中等或低体外微粒体清除率。虽然它们不能抑制伯氏疟原虫在体内的增殖，药代动力学和接触时间的数据提供了一个基准的化合物的配置文件可能需要实现抗疟原虫活性的小鼠，并应促进铅优化。
Malaria-causing Plasmodium parasites are developing resistance to antimalarial drugs, providing the impetus for new antiplasmodials. Although pantothenamides show potent antiplasmodial activity, hydrolysis by pantetheinases/vanins present in blood rapidly inactivates them. We herein report the facile synthesis and biological activity of a small library of pantothenamide analogues in which the labile amide group is replaced with a heteroaromatic ring. Several of these analogues display nanomolar antiplasmodial activity against Plasmodium falciparum and/or Plasmodium knowlesi, and are stable in the presence of pantetheinase. Both a known triazole and a novel isoxazole derivative were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although they fail to suppress Plasmodium berghei proliferation in vivo, the pharmacokinetic and contact time data presented provide a benchmark for the compound profile likely required to achieve antiplasmodial activity in mice and should facilitate lead optimization.