Bouton Jakob, Ferreira de Almeida Fiuza Ludmila, Cardoso Santos Camila, Mazzarella Maria Angela, Soeiro Maria de Nazaré Correia, Maes Louis, Karalic Izet, Caljon Guy, Van Calenbergh Serge
Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Brazil.
J Med Chem. 2021 Apr 8;64(7):4206-4238. doi: 10.1021/acs.jmedchem.1c00135. Epub 2021 Mar 30.
Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3'-position led to analogues with potent anti- brucei and anti- activities. In this work, we report the design and synthesis of pyrazolo[3,4-]pyrimidine nucleosides with 3'- and 7-modifications and assess their potential as anti- and antileishmanial agents. One compound was selected for evaluation in an acute Chagas disease mouse model.
恰加斯病和内脏利什曼病是两种被忽视的热带疾病，在全球造成众多死亡。对于这两种疾病，目前的治疗方法大多不足，因此持续需要发现新药物。由于这两种动质体寄生虫都不能进行嘌呤合成，它们依赖嘌呤补救途径，从宿主获取并加工嘌呤以满足自身需求。因此，嘌呤核苷类似物构成了潜在抗寄生虫药物的合理来源。早期对天然产物杀结核菌素（7-脱氮腺苷）的优化工作，涉及对核苷碱基7位和呋喃核糖3'位的修饰，得到了具有强效抗布鲁氏菌和抗锥虫活性的类似物。在这项工作中，我们报告了具有3'位和7位修饰的吡唑并[3,4-d]嘧啶核苷的设计与合成，并评估了它们作为抗锥虫和抗利什曼原虫药物的潜力。选择了一种化合物在急性恰加斯病小鼠模型中进行评估。
