In vivo trypanosomicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against acute and chronic phases of Chagas disease.
Sánchez-Moreno, Manuel;
Sanz, Ana M;
Gómez-Contreras, Fernando;
Navarro, Pilar;
Marín, Clotilde;
Ramírez-Macias, Inmaculada;
Rosales, María Jose;
Olmo, Francisco;
Garcia-Aranda, Isabel;
Campayo, Lucrecia;
+3 more...Cano, Carmen;
Arrebola, Francisco;
Yunta, María JR;
(2011)
In vivo trypanosomicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against acute and chronic phases of Chagas disease.
Journal of medicinal chemistry, 54 (4).
pp. 970-979.
ISSN 0022-2623
DOI: https://doi.org/10.1021/jm101198k
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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.