Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain.
J Med Chem. 2011 Feb 24;54(4):970-9. doi: 10.1021/jm101198k. Epub 2011 Jan 13.
The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.
已经研究了基于咪唑的苯并[g]酞嗪衍生物 1-4 和新的相关吡唑基化合物 5 和 6 在恰加斯病的急性和慢性阶段的体内杀锥虫活性。通常，化合物 1-6 在疾病的两个阶段比苯并硝唑更有效且毒性更小，并且单取代衍生物 2、4 和 6 比其双取代类似物更有效。通过考虑它们对 Fe-SOD 酶的抑制作用、排泄代谢物的性质和产生的超微结构改变，探索了化合物 1-6 对寄生虫的可能作用机制。补充的组织病理学分析证实，单取代衍生物比参考药物的毒性更小，基于咪唑的化合物 4 的行为尤其值得注意。
