Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium.
Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7), B-2610, Wilrijk, Belgium.
Eur J Med Chem. 2021 Apr 15;216:113290. doi: 10.1016/j.ejmech.2021.113290. Epub 2021 Feb 16.
Kinetoplastid parasites are the causative agents of neglected tropical diseases with an unmet medical need. These parasites are unable to synthesize the purine ring de novo, and therefore rely on purine salvage to meet their purine demand. Evaluating purine nucleoside analogs is therefore an attractive strategy to identify antikinetoplastid agents. Several anti-Trypanosoma cruzi and anti-Trypanosoma brucei 7-deazapurine nucleosides were previously discovered, with the removal of the 3'-hydroxyl group resulting in a significant boost in activity. In this work we therefore decided to assess the effect of the introduction of a 3'-fluoro substituent in 7-deazapurine nucleosides on the anti-kinetoplastid activities. Hence, we synthesized two series of 3'-deoxy-3'-fluororibofuranosyl and 3'-deoxy-3'-fluoroxylofuranosyl nucleosides comprising 7-deazaadenine and -hypoxanthine bases and assayed these for antiparasitic activity. Several analogs with potent activity against T. cruzi and T. brucei were discovered, indicating that a fluorine atom in the 3'-position is a promising modification for the discovery of antiparasitic nucleosides.
动基体原虫寄生虫是被忽视的热带病的病原体，它们存在未满足的医疗需求。这些寄生虫无法从头合成嘌呤环，因此依赖嘌呤补救途径来满足其嘌呤需求。因此，评估嘌呤核苷类似物是发现抗动基体原虫药物的一种有吸引力的策略。先前已经发现了几种抗克氏锥虫和布氏锥虫的 7-脱氮嘌呤核苷，去除 3'-羟基可显著提高其活性。在这项工作中，我们决定评估在 7-脱氮嘌呤核苷中引入 3'-氟取代基对抗动基体原虫活性的影响。因此，我们合成了两个系列的 3'-脱氧-3'-氟代呋喃核糖核苷和 3'-脱氧-3'-氟代氧杂呋喃核糖核苷，包含 7-脱氮腺嘌呤和 -次黄嘌呤碱基，并对这些化合物进行了抗寄生虫活性检测。发现了一些对 T. cruzi 和 T. brucei 具有强大活性的类似物，这表明在 3'-位引入氟原子是发现抗寄生虫核苷的有前途的修饰。
