5-Nitrofuranes and 5-nitrothiophenes with anti-Trypanosoma cruzi

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• 作者：Alej ; ra Gerpe ; Guzmá ; n Á ; lvarez ; Diego Bení ; tez ; Lucí ; a Boiani ; Martí ; n Quiroga ; Paola Herná ; ndez ; Maximiliano Sortino ; Susana Zacchino ; Mercedes Gonzá ; lez ; Hugo Cerecetto
• 关键词：5-Nitrofuran ; 5-Nitrothiophene ; Sterol biosynthesis inhibitors ; Squalene epoxidase ; Anti-Trypanosoma cruzi compounds
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：1 November 2009
• 年：2009
• 卷：17
• 期：21
• 页码：7500-7509
• 全文大小：410 K

文摘

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 120 h, 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.