Chagas disease is caused by the eukaryote parasite Trypanosoma cruzi. Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution. We synthesized 57 new chalcogen compounds which were evaluated against T. cruzi, C2C12 cells and cruzain, the main target of this parasite. Additionally, human cathepsin L, was tested for selectivity. Three compounds were selected, based on their activity against the intracellular amastigotes (EC₅₀ < 1 μM, SI > 10) and cruzain (IC₅₀ < 100 nM, SI > 5.55) which compared favorably with the approved drug, Benznidazole, and the well-established cruzain inhibitor K777. Seleno-compounds demonstrated enhanced activity and selenazoles showed a decrease in selenium-associated toxicity. Compound 4-methyl-2-(2-(1-(3-nitrophenyl)ethylidene)hydrazineyl)-1,3-selenazole (Se2h) emerged as a promising candidate, and its binding to cruzain was investigated. Pharmacokinetic assessment was conducted, showing a favorable profile for subsequent in vivo assays.

中文翻译：

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新型硫族氨基脲 （S， Se） 及其唑类衍生物的合成及生物学评价


美洲锥虫病是由真核生物寄生虫克氏锥虫引起的。目前的治疗方法疗效有限，而硒基化合物成为新疗法的有前途的候选者，其生物等价物硫正在超越。我们使用等位取代设计了新的硫代氨基甲酮、噻唑类、硒代氨基甲酸酯类和色那唑类。我们合成了 57 种新的硫属化合物，这些化合物针对克氏锥虫、C2C12 细胞和该寄生虫的主要靶标克鲁扎因进行了评估。此外，还检测了人组织蛋白酶 L 的选择性。根据它们对细胞内无毛体 （EC₅₀ < 1 μM， SI > 10） 和 cruzain （IC₅₀ < 100 nM， SI > 5.55） 的活性，选择了三种化合物，与批准的药物 Benznidazole 和成熟的 Cruzain 抑制剂 K777 相比具有优势。硒化合物表现出增强的活性，而硒唑显示出硒相关毒性的降低。化合物 4-甲基-2-（2-（1-（3-硝基苯基）亚乙基）酰肼基）-1,3-硒唑 （Se2h） 成为一种有前途的候选化合物，并研究了其与克鲁扎因的结合。进行了药代动力学评估，显示出对后续体内测定的良好特征。