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首页> 美国卫生研究院文献>Scientific Reports >A semi-synthetic neolignan derivative from dihydrodieugenol B selectively affects the bioenergetic system of Leishmania infantum and inhibits cell division
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A semi-synthetic neolignan derivative from dihydrodieugenol B selectively affects the bioenergetic system of Leishmania infantum and inhibits cell division

机译：来自二氢丁二酚B的半合成新木脂素衍生物选择性影响婴儿利什曼原虫的生物能系统并抑制细胞分裂

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摘要

Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. Plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha, and their effects against intracellular amastigotes of Leishmania (L.) infantum evaluated in vitro. IC50 values between 6 and 35 µM were observed and in silico predictions suggested good oral bioavailability, no PAINS similarities, and ADMET risks typical of lipophilic compounds. The most selective (SI > 32) compound was chosen for lethal action and immunomodulatory studies. This compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca2+, possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania, inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies.
机译：利什曼病是一种被忽视的疾病，仅用有限的治疗方法即可影响超过1200万人。植物来源的天然产物代表了抗原生动物原型的有用来源。在这项工作中，从巴西植物Nectandra leucantha中分离出的新木脂素制备了四种衍生物，并在体外评估了它们对婴儿利什曼原虫（L.）婴儿胞内变形虫的作用。观察到IC50值介于6至35µM之间，并且计算机模拟预测表明其口服生物利用度良好，没有PAINS相似性，并且具有亲脂性化合物典型的ADMET风险。选择最具选择性（SI> 32）的化合物进行致死作用和免疫调节研究。该化合物引起质膜电位瞬时去极化，并引起细胞内Ca 2 + 失衡，可能导致线粒体损伤，导致膜电位强烈去极化并降低ATP水平。该衍生物还干扰了利什曼原虫的细胞周期，诱导了程序性的细胞死亡样机制并影响了DNA复制。进一步的免疫调节研究表明，该化合物通过宿主细胞的独立激活消除了amastigotes，同时降低了IL-10，TNF和MCP-1的水平。另外，该衍生物在鼠类红细胞中没有引起溶血作用，可以被认为有希望用于未来的铅研究。

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