Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages
Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages
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DOI：
10.1016/j.cbi.2017.08.017
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发表时间：
2017-11-01
影响因子：
5.1
通讯作者：
Lago, Joao Henrique G.
中科院分区：
文献类型：
--
作者：
Grecco, Simone S.;Costa-Silva, Thais A.;Lago, Joao Henrique G.
恰加斯病是一种被忽视的热带疾病，由原生动物寄生虫克氏锥虫引起，影响热带和亚热带国家（尤其是拉丁美洲）超过 800 万人。目前的治疗仅限于硝呋莫司和苯并硝唑，两者的疗效均较低且毒性较高。在这项工作中，Nectandra leucantha（樟科）叶子的正己烷提取物表现出针对克氏锥虫的体外抗锥虫活性。通过几个色谱步骤，分离出四种相关的新木脂素，并进行化学表征为脱氢二丁香酚 B (1)， 1-(8-丙烯基)-3-[3'-甲氧基-1'-(8-丙烯基)-苯氧基]-4,5-二甲氧基苯(2)、1-[(7S)-羟基-8-丙烯基]-3-[3'-甲氧基-1'-(8'-丙烯基)-苯氧基]-4羟基-5-甲氧基苯(3)，和1-[(7S)-羟基-8-丙烯基]-3-[3'-甲氧基-1'-(8'-丙烯基)-苯氧基]-4,5-二甲氧基苯(4)。这些化合物针对克氏锥虫的细胞内无鞭毛体和细胞外锥鞭毛体以及哺乳动物细胞毒性进行了测试。 Neolignan 4 对克氏锥虫的锥鞭毛体 (>5) 和无鞭毛体 (>13) 显示出较高的选择性指数 (SI)。作用机制的研究表明，新木脂素 4 引起质膜通透性的显着改变，以及锥鞭毛体形式的线粒体功能障碍。药代动力学和毒性 (ADMET) 特性的计算机研究预测，所有化合物都是非诱变、非致癌、非遗传毒性的弱 hERG 阻滞剂，具有可接受的分布容积 (1.66-3.32 L/kg) 和低啮齿动物口服毒性 (LD50 810-e2200 mg/kg)。考虑到脑恰加斯病的一些临床事件，这些化合物还表现出有利的特性，例如血脑屏障渗透性。还预测了不利的特性，如 P450 同工型的高度混杂、高血浆蛋白结合亲和力 (>91%) 以及中等到低的口服生物利用度。最后，没有任何分离的新木脂素被预测为干扰化合物（PAINS）。考虑到分离的新木脂素具有良好的化学和生物学特性，这些化合物可以作为开发治疗南美锥虫病的新先导化合物的起点。 (C) 2017 Elsevier B.V. 保留所有权利。
Chagas disease is a neglected tropical disease, caused by the protozoan parasite Trypanosoma cruzi, which affects more than eight million people in Tropical and Subtropical countries especially in Latin America. Current treatment is limited to nifurtimox and benznidazole, both with reduced effectiveness and high toxicity. In this work, the n-hexane extract from leaves of Nectandra leucantha (Lauraceae) displayed in vitro antitrypanosomal activity against T. cruzi.Using several chromatographic steps, four related neolignans were isolated and chemically characterized as dehydrodieugenol B (1), 1-(8-propenyl)-3-[3'-methoxy-1'-(8-propenyl)-phenoxy]-4,5dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4hydroxy-5-methoxybenzene (3), and 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4,5-dimethoxybenzene (4). These compounds were tested against intracellular amastigotes and extracellular trypomastigotes of T. cruzi and for mammalian cytotoxicity. Neolignan 4 showed the higher selectivity index (SI) against trypomastigotes (>5) and amastigotes (>13) of T. cruzi. The investigation of the mechanism of action demonstrated that neolignan 4 caused substantial alteration of the plasma membrane permeability, together with mitochondrial dysfunctions in trypomastigote forms. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were non-mutagenic, non-carcinogenic, non-genotoxic, weak hERG blockers, with acceptable volume of distribution (1.66-3.32 L/kg), and low rodent oral toxicity (LD50 810-e2200 mg/kg). Considering some clinical events of cerebral Chagas disease, the compounds also demonstrated favorable properties, such as blood-brain barrier penetration. Unfavorable properties were also predicted as high promiscuity for P450 isoforms, high plasma protein binding affinity (>91%), and moderate-to-low oral bioavailability. Finally, none of the isolated neolignans was predicted as interference compounds (PAINS). Considering the promising chemical and biological properties of the isolated neolignans, these compounds could be used as starting points to develop new lead compounds for Chagas disease. (C) 2017 Elsevier B.V. All rights reserved.