PDF(Pubmed)
Abstract：
For decades, only two nitroheterocyclic drugs have been used as therapeutic agents for Chagas disease. However, these drugs present limited effectiveness during the chronic phase, possess unfavorable pharmacokinetic properties, and induce severe adverse effects, resulting in low treatment adherence. A previous study reported that N-(cyclohexylcarbamothioyl) benzamide (BTU-1), N-(tert-butylcarbamothioyl) benzamide (BTU-2), and (4-bromo-N-(3-nitrophenyl) carbamothioyl benzamide (BTU-3) present selective antiprotozoal activity against all developmental forms of Trypanosoma cruzi Y strain. In this study, we investigated the mechanism of action of these compounds through microscopy and biochemical analyses. Transmission electron microscopy analysis showed nuclear disorganization, changes in the plasma membrane with the appearance of blebs and extracellular arrangements, intense vacuolization, mitochondrial swelling, and formation of myelin-like structures. Biochemical results showed changes in the mitochondrial membrane potential, reactive oxygen species content, lipid peroxidation, and plasma membrane fluidity. In addition, the formation of autophagic vacuoles was observed. These findings indicate that BTU-1, BTU-2, and BTU-3 induced profound morphological, ultrastructural, and biochemical alterations in epimastigote forms, triggering an autophagic-dependent cell death pathway.
摘要：
几十年来,只有两种硝基杂环药物被用作恰加斯病的治疗剂。然而,这些药物在慢性期效果有限，具有不利的药代动力学特性，并引起严重的不良反应，导致治疗依从性低。以前的研究报道，N-（环己基氨基甲酰基）苯甲酰胺（BTU-1），N-(叔丁基氨基甲酰基)苯甲酰胺(BTU-2)，和（4-溴-N-（3-硝基苯基）氨基甲酰基苯甲酰胺（BTU-3）对所有发育形式的锥虫Y菌株均具有选择性的抗原生动物活性。在这项研究中,我们通过显微镜和生化分析研究了这些化合物的作用机理。透射电镜分析显示核解体，随着气泡和细胞外排列的出现，质膜的变化，强烈的空泡化，线粒体肿胀,和髓鞘样结构的形成。生化结果显示线粒体膜电位的变化,活性氧含量，脂质过氧化，和质膜流动性。此外,观察到自噬液泡的形成。这些发现表明BTU-1，BTU-2和BTU-3诱导了深刻的形态学，超微结构，和epimastigote形式的生化改变，触发自噬依赖性细胞死亡途径。
