Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
J Med Chem. 2012 May 10;55(9):4231-43. doi: 10.1021/jm2017144. Epub 2012 Apr 24.
The in vitro and in vivo anti- Trypanosoma cruzi activity of the pyrazole-containing macrobicyclic polyamine 1 and N-methyl- and N-benzyl-substituted monocyclic polyamines 2 and 3 was studied. Activity against both the acute and chronic phases of Chagas disease was considered. The compounds were more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, but 1 and 2 were especially effective, where cryptand 1 was the most active, particularly in the chronic phase. The activity results found for these compounds were complemented and discussed by considering their inhibitory effect on the iron superoxide dismutase enzyme of the parasite, the nature of the metabolites excreted after treatment, and the ultrastructural alterations produced. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug and that 1 and 2 exhibited lower levels of damage than 3.
研究了含吡唑的大环多胺 1 和 N-甲基-和 N-苄基取代的单环多胺 2 和 3 的抗 Trypanosoma cruzi 的体外和体内活性。考虑了对恰加斯病的急、慢性期的活性。与参考药物苯唑达唑相比，这些化合物对寄生虫的活性更高，对 Vero 细胞的毒性更低，但 1 和 2 特别有效，其中 cryptand 1 的活性最高，特别是在慢性期。通过考虑这些化合物对寄生虫铁超氧化物歧化酶的抑制作用、治疗后排泄的代谢物的性质以及产生的超微结构改变，对这些化合物的活性结果进行了补充和讨论。补充的组织病理学分析证实，与参考药物相比，测试的化合物对哺乳动物的毒性明显降低，并且 1 和 2 比 3 造成的损害程度更低。
