Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez, S/N, La Laguna, Tenerife, Islas Canarias 38203, Spain; Red de Investigación Colaborativa en Enfermedades Tropicales (RICET); Departement of Biology, Sidi Mohamed Ben Abdellah University, Faculty of Sciences and Techniques, Laboratory of Microbial Biotechnology and Bioactive Molecules, PB 2202, Fez, Morocco.
Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez, S/N, La Laguna, Tenerife, Islas Canarias 38203, Spain; Red de Investigación Colaborativa en Enfermedades Tropicales (RICET); Departamento de Obstetricia, Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad De La Laguna, La Laguna, Tenerife, Islas Canarias 38203, Spain.
Biomed Pharmacother. 2020 Oct;130:110518. doi: 10.1016/j.biopha.2020.110518. Epub 2020 Jul 13.
Neglected tropical diseases such as leishmaniasis and American trypanosomiasis represent an increasing health problem. Current treatments are not satisfactory which remains an urgent need for novel, cheap and safe chemotherapies. In the course of our ongoing search for new potential anti-protozoal agents, this study aimed to perform a bio-guided fractionation of Inula viscosa (Asteraceae) using in vitro assays against three strains of Leishmania and Trypanosma genus. Eight known compounds were identified from the ethanolic extract of leaves, sesquiterpenoids (3 and 4) and flavonoids (5 and 6) were characterized as the main bioactive constituents. Sesquiterpene lactones 3 and 4 (IC values between 4.99 and 14.26 μM) showed promising antiparasitic activity against promastigotes of L. donovani, L. amazonensis and epimastigotes of T. cruzi. Their structures were successfully characterized by spectroscopic techniques including 1D and 2D NMR experiments. Furthermore, the main bioactive compounds 4, 5 and 6 displayed higher potency (IC values between 0.64 and 2.13 μM) against amastigotes of L. amazonensis than miltefosine (IC 3.11 μM), and a low toxicity on macrophages cell line (SI > 45). The analysis of structure-activity relationship (SAR) of the anti-protozoal activity revealed that lactonization or oxidation enhanced the biological profile, suggesting that the hydrophobic moiety was presumably involved in the activity by increasing the affinity and/or cell membrane permeability. In order to get an insight into the mechanism of action of these compounds, programmed cell death (PCD) experiments were performed, and the obtained results suggest that the reported compounds induced PCD in the treated parasites. These results highlight that sesquiterpenoids and flavonoids from I. viscosa could constitute an interesting scaffold for the development of novel antikinetoplastid agents.
利什曼病和美洲锥虫病等被忽视的热带病是日益严重的健康问题。目前的治疗方法并不令人满意，因此迫切需要新型、廉价和安全的化疗药物。在我们正在进行的寻找新的潜在抗原生动物药物的过程中，本研究旨在使用针对三种利什曼原虫和锥虫属的体外测定法对旋覆花（菊科）进行生物导向分离。从叶的乙醇提取物中鉴定出八种已知化合物，为倍半萜（3 和 4）和黄酮类化合物（5 和 6），被鉴定为主要的生物活性成分。倍半萜内酯 3 和 4（IC 值在 4.99 和 14.26 μM 之间）对 L. donovani、L. amazonensis 的前鞭毛体和 T. cruzi 的epimastigotes 表现出有希望的抗寄生虫活性。它们的结构通过包括 1D 和 2D NMR 实验在内的光谱技术成功表征。此外，主要生物活性化合物 4、5 和 6 对 L. amazonensis 的无鞭毛体的活性更强（IC 值在 0.64 和 2.13 μM 之间），优于米替福新（IC 3.11 μM），并且对巨噬细胞系的毒性较低（SI > 45）。对抗原生动物活性的结构-活性关系（SAR）分析表明，内酯化或氧化增强了生物特征，这表明疏水性部分可能通过增加亲和力和/或细胞膜通透性来参与活性。为了深入了解这些化合物的作用机制，进行了程序性细胞死亡（PCD）实验，结果表明，所报道的化合物在处理的寄生虫中诱导了 PCD。这些结果表明，旋覆花的倍半萜和黄酮类化合物可能为开发新型抗锥虫药物提供一个有趣的骨架。
