Abstract
Today, there are approximately 8 million cases of Chagas disease in the southern cone of South America alone, and about 100 million people are living with the risk of becoming infected. The present pharmacotherapy is sometimes ineffective and has serious side effects. Here, we report a series of 4,5-dihydroisoxazoles incorporating hydroxamate moieties, which act as effective inhibitors of the carbonic anhydrase (CA) from Trypanosoma cruzi (TcCA). One compound (5g) was evaluated in detail and shows promising features as an antitrypanosomal agent. Excellent values for the inhibition of growth for all three developmental forms of the parasite were observed at low concentrations of 5g (IC50 values from 7.0 to <1 μM). The compound has a selectivity index (SI) of 6.7 and no cytotoxicity to macrophage cells. Preliminary in vivo data showed that 5g reduces bloodstream parasites and that all treated mice survived; it was also more effective than the standard drug benznidazole.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carbonic Anhydrase Inhibitors / chemical synthesis*
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Carbonic Anhydrase Inhibitors / chemistry
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Carbonic Anhydrase Inhibitors / pharmacology
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Carbonic Anhydrases / metabolism
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Cell Line, Tumor
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Chagas Disease / drug therapy*
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Chagas Disease / parasitology
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Drug Design
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / parasitology
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Mice
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Mice, Inbred BALB C
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Peptide Hydrolases / metabolism
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Structure-Activity Relationship
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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
Substances
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Carbonic Anhydrase Inhibitors
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Hydroxamic Acids
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Isoenzymes
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Isoxazoles
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Protease Inhibitors
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Trypanocidal Agents
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Peptide Hydrolases
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Carbonic Anhydrases