Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium.
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Belgium.
Int J Parasitol Drugs Drug Resist. 2021 Dec;17:57-66. doi: 10.1016/j.ijpddr.2021.08.001. Epub 2021 Aug 6.
Kinetoplastid parasites are the causative agents of Chagas disease (CD), leishmaniasis and human African trypanosomiasis (HAT). Despite a sustained decrease in the number of HAT cases, more efforts are needed to discover safe and effective therapies against CD and leishmaniasis. Kinetoplastid parasites lack the capability to biosynthesize purines de novo and thus critically depend on uptake and processing of purines from host cells. As such, modified purine nucleoside analogues may act as broad-spectrum antikinetoplastid agents. This study assessed the in vitro activity profile of 7-modified 6-methyl tubercidin derivatives against Trypanosoma cruzi, Leishmania infantum, Trypanosoma brucei brucei and T. b. rhodesiense, and led to the identification of analogues that display activity against all these species, such as 7-ethyl (13) and 7-chloro (7) analogues. These selected analogues also proved sufficiently stable in liver microsomes to warrant in vivo follow-up evaluation.
动基体原虫是恰加斯病（CD）、利什曼病和人类非洲锥虫病（HAT）的病原体。尽管 HAT 病例数量持续减少，但仍需要更多努力来发现针对 CD 和利什曼病的安全有效疗法。动基体原虫缺乏从头生物合成嘌呤的能力，因此严重依赖于从宿主细胞摄取和处理嘌呤。因此，修饰的嘌呤核苷类似物可以作为广谱抗动基体原虫药物。本研究评估了 7 种修饰的 6-甲基胸苷衍生物对克氏锥虫、婴儿利什曼原虫、布氏锥虫和罗德西亚锥虫的体外活性谱，鉴定出了对所有这些物种均具有活性的类似物，如 7-乙基（13）和 7-氯（7）类似物。这些选定的类似物在肝微粒体中也足够稳定，值得进行后续的体内评估。
