Design, Synthesis, and Evaluation of Hydroxamic Acid Derivatives as Promising Agents for the Management of Chagas Disease

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• 作者：Giseli Capaci Rodrigues ; Daniel Ferreira Feijó ; Marcelo Torres Bozza ; Peiwen Pan ; Daniela Vullo ; Seppo Parkkila ; Claudiu T. Supuran ; Clemente Capasso ; Alcino Palermo Aguiar ; Alane Beatriz Vermelho
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 23, 2014
• 年：2014
• 卷：57
• 期：2
• 页码：298-308
• 全文大小：473K
• ISSN：1520-4804

文摘

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 渭M). 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.