In Vivo Trypanosomicidal Activity of Imidazole- or Pyrazole-Based Benzo[g]phthalazine Derivatives against Acute and Chronic Phases of Chagas Disease
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- 作者：Manuel Sa虂nchez-Moreno ; Ana M. Sanz ; Fernando Go虂mez-Contreras ; Pilar Navarro ; Clotilde Mari虂n ; Inmaculada Rami虂rez-Macias ; Mari虂a Jose Rosales ; Francisco Olmo ; Isabel Garcia-Aranda ; Lucrecia Campayo ; Carmen Cano ; Francisco Arrebola ; Mari虂a J. R. Yunta
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：February 24, 2011
- 年：2011
- 卷：54
- 期：4
- 页码：970-979
- 全文大小：1066K
- 年卷期：v.54,no.4(February 24, 2011)
- ISSN：1520-4804
文摘
The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1鈭?b>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鈭?b>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鈭?b>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.