The Plasmodium parasites that cause malaria are adept at developing resistance to antimalarial drugs, necessitating the search for new antiplasmodials. Although several amide analogs of pantothenate (pantothenamides) show potent antiplasmodial activity, hydrolysis by pantetheinases (or vanins) present in blood rapidly inactivates them. We report herein the facile synthesis and biological activity of a small library of pantothenamide analogs in which the labile amide group is replaced with a variety of heteroaromatic rings. Several of the new analogs display antiplasmodial activity in the nanomolar range against P. falciparum and/or P. knowlesi in the presence of pantetheinase. A previously reported triazole and an isoxazole derivative presented here 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 we show here that the two compounds fail to suppress proliferation of P. berghei in vivo, pharmacokinetic and contact time data presented provide a benchmark for the compound profile required to achieve antiplasmodial activity in mice and should facilitate lead optimization.

中文翻译：

---

探索杂芳环取代抗疟原虫泛酰胺的不稳定酰胺

引起疟疾的疟原虫寄生虫擅长发展对抗疟药的抗药性，因此有必要寻找新的抗疟原虫药物。尽管泛酸的几种酰胺类似物（泛酰胺）显示出强大的抗疟原虫活性，但血液中存在的泛酸酶（或范宁）的水解作用很快使它们失活。我们在这里报道了泛酰胺类似物的小文库的简便合成和生物学活性，其中不稳定的酰胺基被各种杂芳环取代。在泛酶的存在下，几种新的类似物在纳摩尔范围内对恶性疟原虫和/或诺氏疟原虫显示出抗疟原虫活性。本文进一步介绍了先前报道的三唑和异恶唑衍生物，并发现它们具有较高的选择性指数，Caco-2通透性中等或较高，体外微粒体清除率中等或较低。尽管我们在这里显示了这两种化合物在体内均不能抑制伯氏疟原虫的增殖，但所提供的药代动力学和接触时间数据为在小鼠中实现抗血浆活性所需的化合物概况提供了基准，并且应有助于铅的优化。