Research School of Biology, Australian National University, Canberra, ACT, Australia.
Department of Chemistry, McGill University, Montreal, Quebec, Canada, H3A 0B8.
Eur J Med Chem. 2024 Dec 15;280:116902. doi: 10.1016/j.ejmech.2024.116902. Epub 2024 Sep 26.
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.
几乎每一种针对疟原虫引起的疟疾的治疗药物都出现了耐药性，这强调了我们迫切需要新的抗疟药物。尽管泛酰巯基乙胺在体外具有高效力和低细胞毒性，但由于人血清中的 pantetheinase 介导的水解作用，其临床应用受到阻碍。我们在此报告了一系列新的泛酰巯基乙胺类似物的化学合成和生物学活性，其中不稳定的酰胺基团被异噁唑环取代。此外，我们首次利用酶促后期多样化生成了额外的含有异噁唑环的泛酰巯基乙胺类似物。生成了 13 种新型含有异噁唑环的泛酰巯基乙胺类似物，其中几种对恶性疟原虫具有纳摩尔级别的抗疟活性，并且在体外对人细胞无毒性。尽管通过后期多样化生成的衍生物的效力不如母体化合物，但最有效的化合物仍然通过干扰泛酸利用过程发挥作用，并且似乎对人细胞无毒。这增加了使用后期多样化来修饰泛酰巯基乙胺类似物的吸引力，可能会产生具有改善的抗疟和/或药理学特性的化合物。
