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首页> 外文期刊>Parasitology >Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi bloodstream trypomastigotes
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Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi bloodstream trypomastigotes

机译：表征两种5-硝基吲唑啉酮原型对锥虫锥虫血锥虫的作用方式的生物学方法

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摘要

The phenotypic activity of two 5-nitroindazolinones, i.e. 2-benzyl-1-propyl (22) and 2-benzyl-1-butyl (24) derivatives, previously proposed as anti-Trypanosoma cruzi prototypes, was presently assayed on bloodstream trypomastigotes (BT) of the moderately drug-resistant Y strain. Further exploration of putative targets and cellular mechanisms involved in their activity was also carried out. Therefore, transmission electron microscopy, high-resolution respirometry and flow cytometry procedures were performed on BT treated for up to 24 h with the respective EC50 value of each derivative. Results demonstrated that although 22 and 24 were not as active as benznidazole in this in vitro assay on BT, both compounds triggered important damages in T. cruzi that lead to the parasite death. Ultrastructural alterations included shedding events, detachment of plasma membrane and nuclear envelope, loss of mitochondrial integrity, besides the occurrence of a large number of intracellular vesicles and profiles of endoplasmic reticulum surrounding cytoplasmic organelles such as mitochondrion. Moreover, both derivatives affected mitochondrion leading to this organelle dysfunction, as reflected by the inhibition in oxygen consumption and the loss of mitochondrial membrane potential. Altogether, the findings exposed in the present study propose autophagic processes and mitochondrial machinery as part of the mode of action of both 5-nitroindazolinones 22 and 24 on T. cruzi trypomastigotes.
机译：目前已在血锥虫（BT）上测定了两种5-硝基吲唑啉酮的表型活性，即先前被提议作为抗台氏锥虫的原型的2-苄基-1-丙基（22）和2-苄基-1-丁基（24）衍生物。 ）中度耐药的Y株。还进行了对推测的靶标和参与其活性的细胞机制的进一步探索。因此，在经过BT处理长达24 h的BT上执行透射电子显微镜，高分辨率呼​​吸测定法和流式细胞术程序，每种衍生物的各自EC50值。结果表明，尽管在BT体外试验中22和24的活性不如苯硝唑，但这两种化合物均对克鲁维氏锥虫造成了重要的损害，导致寄生虫死亡。超微结构的改变包括脱落事件，质膜和核膜的脱落，线粒体完整性的丧失，除了大量胞内囊泡的出现和胞质细胞器（如线粒体）周围的内质网的分布。而且，这两种衍生物都影响线粒体，导致这种细胞器功能障碍，这可以通过抑制耗氧量和线粒体膜电位的丧失来体现。总之，本研究中暴露的发现提出了自噬过程和线粒体机制，作为5-硝基吲唑啉酮22和24对T. cruzi trypomastigotes作用方式的一部分。

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