The emergence of resistance to nearly every therapeutic agent directed against malaria-causing Plasmodium parasites emphasises the dire need for new antimalarials. Despite their high potency and low cytotoxicity in vitro, the clinical use of pantothenamides is hindered by pantetheinase-mediated hydrolysis in human serum. We herein report the chemical synthesis and biological activity of a new series of pantothenamide analogues in which the labile amide group is replaced with an isoxazole ring. In addition, we utilised, for the first time, enzymatic late-stage diversification to generate additional isoxazole-containing pantothenamide-mimics. Thirteen novel isoxazole-containing pantothenamide-mimics were generated, several of which display nanomolar antiplasmodial activity against Plasmodium falciparum and are non-toxic to human cells in vitro. Although the derivatives generated via late-stage diversification are less potent than the parent compounds, the most potent still exerted its activity via a mechanism that interferes with the pantothenate-utilising process and appears to be nontoxic to human cells. This increases the appeal of using late-stage diversification to modify pantothenamide-mimics, potentially leading to compounds with improved antiplasmodial and/or pharmacological properties.

中文翻译：

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具有抗质体活性的新型泛酸类似物的化学合成和酶促后期多样化


对几乎所有针对引起疟疾的疟原虫寄生虫的治疗药物的耐药性的出现凸显了对新型抗疟药的迫切需求。尽管泛酰胺在体外具有高效力和低细胞毒性，但泛肽酶介导的人血清水解阻碍了泛肽的临床使用。我们在此报道了一系列新的泛酰胺类似物的化学合成和生物活性，其中不稳定酰胺基团被异恶唑环取代。此外，我们首次利用酶促后期多样化来生成额外的含异恶唑的泛酰胺模拟物。生成了 13 种新型含异恶唑的泛酰胺模拟物，其中几种对恶性疟原虫具有纳摩尔抗疟原虫活性，并且在体外对人体细胞无毒。尽管通过后期多样化产生的衍生物不如母体化合物有效，但最有效的衍生物仍然通过干扰泛酸利用过程的机制发挥其活性，并且似乎对人体细胞无毒。这增加了使用后期多样化来修饰泛酰胺模拟物的吸引力，从而可能产生具有改进抗疟原虫和/或药理学特性的化合物。