Laboratório de Síntese Orgânica, Departamento de Química, Instituto Militar de Engenharia, IME , Rio de Janeiro, Brasil.
J Med Chem. 2014 Jan 23;57(2):298-308. doi: 10.1021/jm400902y. Epub 2013 Dec 13.
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.
目前，仅在南美洲南部锥体地区，就约有 800 万例恰加斯病，约有 1 亿人面临感染风险。目前的药物治疗有时无效且有严重的副作用。在这里，我们报告了一系列包含羟肟酸部分的 4,5-二氢异恶唑，它们可有效抑制克氏锥虫（TcCA）的碳酸酐酶（CA）。详细评估了一种化合物（5g），它作为抗变形虫剂具有有前景的特征。在低浓度 5g 时观察到对寄生虫所有三种发育形式的生长抑制的优异值（IC50 值为 7.0 至<1 μM）。该化合物的选择性指数（SI）为 6.7，对巨噬细胞无细胞毒性。初步的体内数据表明，5g 可减少血液寄生虫，并且所有接受治疗的小鼠均存活；它也比标准药物苯并咪唑更有效。
