BACKGROUND Chagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds. METHODS Trypanocidal activity: Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50). Toxicity assays: Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure. Structure-activity relationship: A classificatory model was built using 3D descriptors. RESULTS Two of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds. CONCLUSION Two coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.

中文翻译：

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新型香豆素对克氏锥虫有活性，并使用动物模型秀丽隐杆线虫进行毒性评估。

背景技术恰加斯病(CD)是一种热带寄生虫病。尽管感染人数非常多，但可用于治疗克罗恩病的唯一药物硝呋替莫 (Nfx) 和苯硝唑具有剧毒，特别是在疾病的慢性阶段。香豆素是一大类化合物，具有多种有趣的生物特性，例如抗寄生虫。因此，本工作的目的是寻找一种毒性较小的良好抗锥虫药物。使用简单的生物体模型对于规划和简化有效的药物发现变得越来越有吸引力。在这些模型中，秀丽隐杆线虫已成为一种方便且多功能的工具，在新化合物的毒理学潜力鉴定方面具有显着优势。方法 杀锥虫活性：以 50% 抑制浓度 (IC50) 测定 42 种 4-甲氨基香豆素对上鞭毛体形式的克氏锥虫（Tulahuen 2 株）的抑制作用。毒性测定：致死剂量50% (LD50) 和身体面积由急性接触后的秀丽隐杆线虫N2 株（野生型）测定。结构-活动关系：使用 3D 描述符构建分类模型。结果 其中两种香豆素与 Nifurtimox (IC50 = 5.0 ± 1 μM) 几乎等价，其值为：11 h (LaSOM 266)、(IC50 = 6.4 ± 1 μM) 和 11 g (LaSOM 231)、(IC50 = 8.2) ±2.3μM）。在秀丽隐杆线虫中，可以观察到 Nfx 在 LD50 测定和蠕虫发育评估中都显示出更大的毒性。可以观察到 Nfx 和合成化合物（11 小时和 11 g）之间的功效相似。另一方面，Nfx 的毒性大约是其他化合物的三倍。QSAR-3D 研究结果表明，取代基的体积和疏水性对衍生物的杀锥虫活性有显着影响，可抑制 50% 以上。这些结果表明，线虫模型对于筛选潜在有毒化合物是有效的。结论 两种香豆素（11 h 和 11 g）对克氏锥虫上鞭毛体的活性与硝呋替莫相似，但 LD50 和秀丽隐杆线虫试验的毒性较低。这两种化合物可能是开发新的杀锥虫药物的可行起点。