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15β-齐墩果酸氧基-贝壳杉烯-16-烯-19-酸,一种从 中分离得到的二萜,作为治疗血吸虫病的有前途的口服化合物。

15β-Senecioyl-oxy--kaur-16-en-19-oic Acid, a Diterpene Isolated from , as Promising Oral Compound for the Treatment of Schistosomiasis.

机构信息

Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, São Paulo 09210-180, Brazil.

Núcleo de Pesquisa em Doenças Negligenciadas, Universidade Guarulhos, Guarulhos, São Paulo 07023-070, Brazil.

出版信息

J Nat Prod. 2020 Dec 24;83(12):3744-3750. doi: 10.1021/acs.jnatprod.0c01050. Epub 2020 Nov 25.

Abstract

Praziquantel is the only available drug to treat schistosomiasis, and therefore, urgent studies must be performed to identify new anthelmintic agents. This study reports the anthelmintic evaluation of two related -kaurane diterpenes isolated from aerial parts of (Asteraceae), -kaur-16-en-19-oic acid () and 15β-senecioyl-oxy--kaur-16-en-19-oic acid () against and in a murine model of schistosomiasis. Both compounds exhibited activity with lethal concentration 50% (LC) values of 26.1 μM () and 11.6 μM () as well as reduced toxicity against human cell lines, revealing a good selectivity profile, mainly with compound (selectivity index > 10). Compound also decreased egg production and caused morphological alterations in the parasite reproductive system. In mice infected with , oral treatment with compound at 400 mg/kg, the standard dose used in this model of schistosomiasis, caused a significant reduction in a total worm burden of 61.9% ( < 0.01). egg production, a key mechanism for both transmission and pathogenesis, was also markedly reduced. In addition, compound achieved a significant reduction in hepatosplenomegaly. Therefore, the diterpene 15β-senecioyl-oxy--kaur-16-en-19-oic acid () has an acceptable cytotoxicity profile and is orally active in a murine schistosomiasis model.

摘要

吡喹酮是唯一可用于治疗血吸虫病的药物,因此必须紧急开展研究,以鉴定新的驱虫药物。本研究报告了两种从 (菊科)的地上部分分离得到的相关贝壳杉烷二萜——贝壳杉-16-烯-19-酸()和 15β-柳酰氧基--贝壳杉-16-烯-19-酸()对 和血吸虫病小鼠模型的驱虫评估。这两种化合物均表现出驱虫活性,半数致死浓度(LC)值分别为 26.1 μM()和 11.6 μM(),对人细胞系的毒性降低,显示出良好的选择性特征,主要是化合物 (选择性指数>10)。化合物 还降低了产卵量,并导致寄生虫生殖系统的形态改变。在感染 的小鼠中,口服给予化合物 400 mg/kg,这是该血吸虫病模型中使用的标准剂量,可导致总虫荷减少 61.9%(<0.01)。这一关键的传播和发病机制机制也明显减少了 卵的产生。此外,化合物 还显著减轻了肝脾肿大。因此,贝壳杉烷二萜 15β-柳酰氧基--贝壳杉-16-烯-19-酸()具有可接受的细胞毒性特征,并且在血吸虫病小鼠模型中具有口服活性。

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