Muro Beatriz, Reviriego Felipe, Navarro Pilar, Marín Clotilde, Ramírez-Macías Inmaculada, Rosales María José, Sánchez-Moreno Manuel, Arán Vicente J
Instituto de Química Médica (IQM), CSIC, c/ Juan de la Cierva 3, E-28006 Madrid, Spain.
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
Eur J Med Chem. 2014 Mar 3;74:124-34. doi: 10.1016/j.ejmech.2013.12.025. Epub 2014 Jan 3.
The synthesis and antiprotozoal activity of some 3-alkoxy-1-alkyl- (1, 4) and 3-alkoxy-1-(ω-aminoalkyl)-5-nitroindazoles (2, 3, 5-8) against different morphological forms of Trypanosoma cruzi are reported. These compounds were prepared using simple alkylation reactions and, usually, taking advantage of the reactivity of some indazole-derived betaines previously studied by us. Most indazole derivatives showed in vitro activities similar or higher than those of the reference drug benznidazole; this fact, along with low unspecific cytotoxicities against Vero cells shown by some of them, led to very good selectivity indexes (SI). The high efficiency of 5-nitroindazoles 1 and 2 against T. cruzi was confirmed by further in vitro studies on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. Complementary analyses of the changes in the metabolites excreted by the parasite and on the ultrastructural alterations induced after treatment with indazole derivatives 1 and 2 were also conducted.
报道了一些3-烷氧基-1-烷基-（1,4）和3-烷氧基-1-（ω-氨基烷基）-5-硝基吲唑（2,3,5-8）对克氏锥虫不同形态的合成及抗原虫活性。这些化合物通过简单的烷基化反应制备，并且通常利用我们之前研究过的一些吲唑衍生的甜菜碱的反应性。大多数吲唑衍生物显示出与参考药物苯硝唑相似或更高的体外活性；这一事实，连同其中一些对Vero细胞显示出的低非特异性细胞毒性，导致了非常好的选择性指数（SI）。5-硝基吲唑1和2对克氏锥虫的高效性通过对感染率的进一步体外研究以及在急性和慢性恰加斯病小鼠模型中的额外体内研究得到证实。还对寄生虫排泄的代谢产物变化以及用吲唑衍生物1和2处理后诱导的超微结构改变进行了补充分析。
