Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
Eur J Med Chem. 2010 Jun;45(6):2154-64. doi: 10.1016/j.ejmech.2010.01.052. Epub 2010 Jan 28.
Chagas disease represents a relevant health problem in Central and South America. The first line of treatment is Nifurtimox and Benznidazole which have a great deal of disadvantages that demands the rapid generation of therapeutic alternatives. Based in our research on aza-thiaheterocycles as anti-Trypanosoma cruzi agents we identified pharmacophores that act through oxidative stress. Here, we describe the synthesis and the activity of new containing bioactive-heterocycles analogues of naftifine as potential T. cruzi membrane sterol biosynthesis inhibitors. Benzimidazole 1,3-dioxides (11 and 13) and quinoxaline 1,4-dioxides (22 and 23) displayed excellent parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated with the compounds showed that any of them are able to accumulate squalene suggesting that in the anti-T. cruzi mechanism of action is not involved the inhibition of sterol biosynthesis. Some derivatives were also tested as antifungal agents. The results obtained in the present work open potential therapeutic possibilities of new compounds for these infectious diseases.
恰加斯病是中美洲和南美洲的一个重要健康问题。一线治疗药物是硝呋替莫和苯并咪唑，但它们有很多缺点，需要迅速开发出治疗替代品。基于我们对氮杂噻唑杂环作为抗克氏锥虫药物的研究，我们确定了通过氧化应激起作用的药效团。在这里，我们描述了作为潜在的克氏锥虫膜甾醇生物合成抑制剂的具有生物活性的新型萘替芬含杂环类似物的合成和活性。苯并咪唑 1,3-二氧化物（11 和 13）和喹喔啉 1,4-二氧化物（22 和 23）显示出优异的寄生虫/哺乳动物选择指数。用化合物孵育寄生虫后的游离甾醇分析表明，它们中的任何一种都能够积累鲨烯，这表明在抗克氏锥虫的作用机制中不涉及甾醇生物合成的抑制。一些衍生物也被测试为抗真菌剂。本工作的结果为这些传染病的新化合物提供了潜在的治疗可能性。
