Laboratory for Medicinal Chemistry (Campus Heymans) , Ghent University , Ottergemsesteenweg 460 , Gent B-9000 , Belgium.
XStruct, Department of Chemistry , Ghent University , Krijgslaan 281 S3 , Gent B-9000 , Belgium.
J Med Chem. 2018 Oct 25;61(20):9287-9300. doi: 10.1021/acs.jmedchem.8b00999. Epub 2018 Oct 3.
Chagas disease is the leading cause of cardiac-related mortality in Latin American countries where it is endemic. Trypanosoma cruzi, the disease-causing pathogen, is unable to synthesize purines de novo, necessitating salvage of preformed host purines. Therefore, purine and purine-nucleoside analogues might constitute an attractive source for identifying antitrypanosomal hits. In this study, structural elements of two purine-nucleoside analogues (i.e., cordycepin and a recently discovered 7-substituted 7-deazaadenosine) led to the identification of novel nucleoside analogues with potent in vitro activity. The structure-activity relationships of substituents at C-7 were investigated, ultimately leading to the selection of compound 5, with a C-7 para-chlorophenyl group, for in vivo evaluation. This derivative showed complete suppression of T. cruzi Y-strain blood parasitemia when orally administered twice daily for 5 days at 25 mg/kg and was able to protect infected mice from parasite-induced mortality. However, sterile cure by immunosuppression could not be demonstrated.
恰加斯病是拉丁美洲国家心脏相关死亡率的主要原因，这些国家是该病的流行地区。引起这种疾病的病原体克氏锥虫（Trypanosoma cruzi）不能从头合成嘌呤，因此需要从宿主中回收预先形成的嘌呤。因此，嘌呤和嘌呤核苷类似物可能成为鉴定抗锥虫药物的有吸引力的来源。在这项研究中，两种嘌呤核苷类似物（即虫草素和最近发现的 7-取代 7-脱氮腺苷）的结构元件导致了具有强大体外活性的新型核苷类似物的鉴定。研究了 C-7 位取代基的构效关系，最终选择了具有 C-7 对位氯苯基取代基的化合物 5 进行体内评价。该衍生物以 25mg/kg 的剂量每天口服两次，连续 5 天，可完全抑制 T. cruzi Y 株血液寄生虫血症，并能保护感染的小鼠免受寄生虫引起的死亡。然而，不能证明通过免疫抑制达到无菌治愈。
