Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chagas Disease / drug therapy*
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Chlorocebus aethiops
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Female
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Histocytochemistry
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Inhibitory Concentration 50
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Magnetic Resonance Spectroscopy
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Mice
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Microscopy, Electron, Transmission
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Phthalazines / chemical synthesis*
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Phthalazines / chemistry
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Phthalazines / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Spectrometry, Mass, Electrospray Ionization
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Spectrophotometry, Infrared
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Structure-Activity Relationship
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Superoxide Dismutase / antagonists & inhibitors
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / chemistry
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Trypanocidal Agents / pharmacology*
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Trypanosoma cruzi / drug effects*
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Trypanosoma cruzi / enzymology
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Trypanosoma cruzi / growth & development
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Trypanosoma cruzi / ultrastructure
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Vero Cells
Substances
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Imidazoles
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Phthalazines
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Pyrazoles
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Trypanocidal Agents
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Superoxide Dismutase