Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
Bioorg Med Chem. 2009 Nov 1;17(21):7500-9. doi: 10.1016/j.bmc.2009.09.013. Epub 2009 Sep 15.
Chagas disease represents a serious public health problem in South America. The first line of treatment is Nifurtimox and Benznidazole which generate toxic effects in treated patients. We have recently shown that a number of 5-nitrofuranes possess activity against Trypanosoma cruzi through oxidative stress and inhibition of parasite ergosterol biosynthesis, specifically at the level of squalene epoxidase. Here, we identify new 5-nitrofuranes and the thia-analogues with excellent effects on the viability of T. cruzi and adequate parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated, during 120h, with the compounds showed that some of them accumulated squalene suggesting the squalene epoxidase activity inhibition of the parasite. Nifurtimox was able to accumulate squalene only at lower incubation times. Due to this fact some derivatives were also tested as antifungal agents. Quantitative structure-activity relationship studies were also performed showing relevant features for further new derivatives design. Taken together, the results obtained in the present work point to a more general effect of 5-nitrofuranes and 5-nitrothiophenes in trypanosomatids, opening potential therapeutic possibilities of them for these infectious diseases.
恰加斯病是南美洲严重的公共卫生问题。一线治疗药物是硝呋莫司和苯并咪唑，它们会在治疗患者中产生毒副作用。我们最近发现，一些 5-硝基呋喃类化合物通过氧化应激和抑制寄生虫麦角固醇生物合成，特别是在鲨烯环氧化酶水平上，具有抗克氏锥虫的活性。在这里，我们鉴定了新的 5-硝基呋喃类化合物和噻唑类似物，它们对 T. cruzi 的存活率具有极好的效果，并且具有适当的寄生虫/哺乳动物选择性指数。对用化合物孵育 120 小时的寄生虫中的游离甾醇进行分析表明，其中一些化合物积累了鲨烯，表明寄生虫的鲨烯环氧化酶活性受到抑制。硝呋莫司仅在较低的孵育时间才能积累鲨烯。由于这个原因，一些衍生物也被测试为抗真菌剂。还进行了定量构效关系研究，显示了进一步设计新衍生物的相关特征。综上所述，本工作获得的结果表明 5-硝基呋喃类化合物和 5-硝基噻吩类化合物在原生动物中有更普遍的作用，为这些传染病提供了它们的潜在治疗可能性。
