Laboratório de Síntese Orgânica Medicinal/LaSOM, Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Laboratório Toxicologia/LATOX, Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
BMC Pharmacol Toxicol. 2019 Dec 19;20(Suppl 1):76. doi: 10.1186/s40360-019-0357-z.
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.
Trypanocidal activity: Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC). Toxicity assays: Lethal dose 50% (LD) 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.
Two of these coumarins demonstrated near equipotency to Nifurtimox (IC = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD 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.
Two coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.
恰加斯病（CD）是一种热带寄生虫病。尽管感染人数非常多，但目前可用的治疗 CD 的药物只有硝呋替莫（Nfx）和苯并咪唑，它们的毒性很高，尤其是在疾病的慢性阶段。香豆素是一大类化合物，具有广泛的有趣的生物特性，如抗寄生虫。因此，本工作的目的是寻找一种毒性较低的良好抗锥虫药物。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，对于新化合物的毒理学潜力鉴定具有显著优势。
抗锥虫活性：用 42 种 4-甲氨基香豆素对 Trypanosoma cruzi（Tulahuen 2 株）的前鞭毛体进行抑制浓度 50%（IC）测定。毒性测定：用 Caenorhabditis elegans N2 株（野生型）在急性暴露后测定半数致死剂量 50%（LD）和体区。构效关系：使用 3D 描述符构建分类模型。
两种香豆素对硝呋替莫的效力相近（IC=5.0±1μM），分别为：11h（LaSOM 266），（IC=6.4±1μM）和 11g（LaSOM 231），（IC=8.2±2.3μM）。在秀丽隐杆线虫中，可以观察到 Nfx 在 LD 测定和对蠕虫发育的评估中表现出更大的毒性。可以观察到 Nfx 与合成化合物（11h 和 11g）之间的疗效相似。另一方面，Nfx 的毒性大约是化合物的三倍。QSAR-3D 研究结果表明，取代基的体积和疏水性对导致抑制率超过 50%的衍生物的抗锥虫活性有显著影响。这些结果表明，秀丽隐杆线虫模型可有效筛选潜在的有毒化合物。
两种香豆素（11h 和 11g）对 T. cruzi 前鞭毛体的活性与硝呋替莫相似，但在 LD 和秀丽隐杆线虫发育测定中毒性较低。这两种化合物可能是开发新的抗锥虫药物的可行起点。
