Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives
Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives
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DOI：
10.1016/j.ejmech.2011.05.035
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发表时间：
2011-09-01
影响因子：
6.7
通讯作者：
Malchiodi, Emilio L.
中科院分区：
文献类型：
--
作者：
Muscia, Gisela C.;Cazorla, Silvia I.;Malchiodi, Emilio L.
研究和开发可有效治疗克氏锥虫感染的新药是美洲1 600万感染者的实际需要。在之前的研究中，被2-胡椒酰甲基取代的喹啉衍生物显示出对恰加斯病有活性，被认为是进一步优化的先导化合物。作为第一种方法，我们对十种类似衍生物进行了一系列的试验。鉴于其令人鼓舞的结果，对其中6种进行了人体血液和细胞内寄生虫复制形式的评估。其中，含有6-乙酰氨基己基取代基的化合物12与结构先导化合物相比，对附乳线虫、锥乳线虫和无尾线虫的活性有显著提高，对存在于人体内的两期寄生虫均有较好的选择性指数。此外，与未治疗的小鼠相比，用化合物12治疗感染小鼠可显著减少寄生虫病。通过计算方法进行分子模拟研究，以阐明决定这些实验生物活性的因素。(C) 2011 Elsevier Masson SAS。版权所有。
Research and development of new drugs effective in the treatment of Trypanosoma cruzi infections are a real need for the 16 million people infected in the Americas. In a previous work, a quinoline derivative substituted by a 2-piperidylmethyl moiety showed to be active against Chagas disease and was considered a lead compound for further optimization. A series of ten analogous derivatives were tested against epimastigotes as a first approach. In view of their promising results, six of them were evaluated against the blood and intracellular replicative forms of the parasite in humans. Among them, compound 12 which possesses a 6-acetamidohexylamino substituent showed remarkable improvement in activity against epimastigotes, trypomastigotes and amastigotes compared with the structure lead, as well as a good selectivity index for the two parasite stages present in humans. In addition, treatment of infected mice with compound 12 induced a significant reduction in parasitemia compared with non-treated mice. Molecular modeling studies were performed by computational methods in order to elucidate the factors determining these experimental bioactivities. (C) 2011 Elsevier Masson SAS. All rights reserved.