Chagas disease (CD) affects more than 6 million people worldwide. The available treatment is far from ideal, creating a demand for new alternative therapies. Botanical diversity provides a wide range of novel potential therapeutic scaffolds. Presently, our aim was to evaluate the mammalian host toxicity and anti-Trypanosoma cruzi activity of botanic natural products including extracts, fractions and purified compounds obtained from Brazilian flora. In this study, 36 samples of extracts and fractions and eight pure compounds obtained from seven plant species were evaluated. The fraction dichloromethane from Aureliana fasciculata var. fasciculata (AFfPD) and the crude extract of Piper tectoniifolium (PTFrE) showed promising trypanosomicidal activity. AFfPD and PTFrE presented EC₅₀ values 10.7 ± 2.8 μg/mL and 12.85 ± 1.52 μg/mL against intracellular forms (Tulahuen strain), respectively. Additionally, both were active upon bloodstream trypomastigotes (Y strain), exhibiting EC₅₀ 2.2 ± 1.0 μg/mL and 38.8 ± 2.1 μg/mL for AFfPD and PTFrE, respectively. Importantly, AFfPD is about five-fold more potent than Benznidazole (Bz), the reference drug for CD, also reaching lower EC₉₀ value (7.92 ± 2.2 μg/mL) as compared to Bz (23.3 ± 0.6 μg/mL). Besides, anti-parasitic effect of eight purified botanic substances was also investigated. Aurelianolide A and B (compounds 1 and 2) from A. fasciculata and compound 8 from P. tuberculatum displayed the best trypanosomicidal effect. Compounds 1, 2 and 8 showed EC₅₀ of 4.6 ± 1.3 μM, 1.6 ± 0.4 μM and 8.1 ± 0.9 μM, respectively against intracellular forms. In addition, in silico analysis of these three biomolecules was performed to predict parameters of absorption, distribution, metabolism and excretion. The studied compounds presented similar ADMET profile as Bz, without presenting mutagenicity and hepatotoxicity aspects as predicted for Bz. Our findings indicate that these natural products have promising anti-T. cruzi effect and may represent new scaffolds for future lead optimization.

中文翻译：

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巴西生物多样性天然产物对克氏锥虫的体外表型活性和硅胶分析

恰加斯病 (CD) 影响全球超过 600 万人。可用的治疗远非理想，从而产生了对新替代疗法的需求。植物多样性提供了广泛的新型潜在治疗支架。目前，我们的目标是评估植物天然产品的哺乳动物宿主毒性和抗克氏锥虫活性，包括从巴西植物群中获得的提取物、馏分和纯化化合物。在本研究中，对 36 种提取物和馏分样品以及从 7 种植物中提取的 8 种纯化合物进行了评估。来自Aureliana fasciculata var. 的二氯甲烷馏分。fasciculata (AFfPD) 和Piper tectoniifolium的粗提取物(PTFrE) 显示出有希望的杀锥虫活性。AFfPD 和 PTFrE针对细胞内形式（Tulahuen 菌株）的EC ₅₀值分别为 10.7 ± 2.8 μg/mL 和 12.85 ± 1.52 μg/mL。此外，两者都对血流锥鞭毛体（Y 株）有活性，AFfPD 和 PTFrE 的EC _{50 分别为}2.2 ± 1.0 μg/mL 和 38.8 ± 2.1 μg/mL。重要的是，AFfPD 的效力是 CD 的参考药物苯并硝唑 (Bz) 的约五倍，与 Bz (23.3 ± 0.6 μg/mL) 相比，其 EC ₉₀值也更低(7.92 ± 2.2 μg/mL)。此外，还研究了八种纯化植物物质的抗寄生虫作用。来自A. fasciculata 的Aurelianolide A 和 B（化合物1和2）和化合物8从P. tuberculatum显示最好trypanosomicidal效果。化合物1，2和8显示出EC ₅₀ 4.6±1.3μM，1.6±0.4μM和8.1±0.9μM，对细胞内的形式。此外，对这三种生物分子进行了计算机模拟分析，以预测吸收、分布、代谢和排泄的参数。所研究的化合物呈现出与 Bz 相似的 ADMET 特征，而没有呈现出 Bz 预测的致突变性和肝毒性方面。我们的研究结果表明，这些天然产物具有有希望的抗克氏锥虫效应，并且可能代表未来铅优化的新支架。