Abstract
New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Protozoan / blood
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Benzoxazoles / chemical synthesis*
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Benzoxazoles / pharmacology
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Benzoxazoles / toxicity
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Cell Line
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Chagas Disease / drug therapy*
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Cysteine Endopeptidases / metabolism
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Female
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Glutathione / metabolism
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Humans
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Macrophages / drug effects
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Mice
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Models, Molecular
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NADH, NADPH Oxidoreductases / metabolism
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Oxidation-Reduction
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Oxygen Consumption / drug effects
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Protozoan Proteins
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Stereoisomerism
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / pharmacology
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Trypanocidal Agents / toxicity
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Trypanosoma cruzi / drug effects*
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Trypanosoma cruzi / enzymology
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Trypanosoma cruzi / physiology
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Vinyl Compounds / chemical synthesis*
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Vinyl Compounds / chemistry
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Vinyl Compounds / pharmacology
Substances
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Antibodies, Protozoan
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Benzoxazoles
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Protozoan Proteins
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Sulfones
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Trypanocidal Agents
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Vinyl Compounds
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benzofuroxan
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NADH, NADPH Oxidoreductases
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trypanothione reductase
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Cysteine Endopeptidases
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cruzipain
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Glutathione