Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi
Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi
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DOI：
10.1016/j.ejmech.2019.05.001
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发表时间：
2019-08-15
影响因子：
6.7
通讯作者：
Tempone, Andre G.
中科院分区：
文献类型：
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作者：
Ferreira, Daiane D.;Sousa, Fernanda S.;Tempone, Andre G.
恰加斯病是一种被忽视的原生动物疾病，影响着发展中国家800多万人。由于目前使用的治疗方法数量和毒性有限，迫切需要新的药物。在以前的研究中，我们报道了两个相关的抗锥虫新木脂素从Nectandra leucantha（樟科）的分离。在这项工作中，一个半合成的23个新木脂素衍生物库的准备，以探索合成可访问的结构活性关系（SAR）对克氏锥虫。五种化合物显示出对锥鞭毛体的活性（IC 50值为8至64 μ M），八种化合物显示出对细胞内无鞭毛体的活性（IC 50值为7至16 μ M）。18种衍生物在高达200 μ M时没有哺乳动物细胞毒性。天然脱氢丁香酚B的酚乙酸酯衍生物对两种寄生虫形式都有效，并消除了巨噬细胞内100%的无鞭毛体。该化合物引起线粒体膜电位快速和强烈的去极化，观察到细胞内活性氧水平降低。荧光分析表明，这种衍生物既不影响渗透性，也不影响寄生质膜的电位，扫描电子显微镜研究也证实了这种效果。结构-活性关系研究（SAR）表明，联芳醚核心上至少有一个烯丙基侧链的存在对抗锥虫活性是重要的，并且游离酚不是必需的。这组新木脂素衍生物代表了未来查加斯病药物发现研究的一个有希望的起点。(C)2019 Elsevier Masson SAS。All rights reserved.
Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 mu M) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 M). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 mu M. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies. (C) 2019 Elsevier Masson SAS. All rights reserved.