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J Med Chem. 2014 Jan 23;57(2):298-308. doi: 10.1021/jm400902y. Epub 2013 Dec 13.

Design, synthesis, and evaluation of hydroxamic acid derivatives as promising agents for the management of Chagas disease.

Author information

1
Laboratório de Síntese Orgânica, Departamento de Química, Instituto Militar de Engenharia, IME , Rio de Janeiro, Brasil.

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.

PMID:
24299463
DOI:
10.1021/jm400902y
[Indexed for MEDLINE]

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