Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21.
Chagas disease is caused by the trypanosomatid parasite Trypanosoma cruzi and threatens millions of lives in South America. As other neglected diseases there is almost no research and development effort by the pharmaceutical industry and the treatment relies on two drugs, Nifurtimox and Benznidazole, discovered empirically more than three decades ago. Nifurtimox, a nitrofurane derivative, is believed to exert its biological activity through the bioreduction of the nitro-group to a nitro-anion radical which undergoes redox-cycling with molecular oxygen. This hypothesis is generally accepted, although arguments against it have been presented. In the present work we studied the ability of Nifurtimox and five N-oxide-containing heterocycles to induce oxidative stress in T. cruzi. N-Oxide-containing heterocycles represent a promising group of new trypanosomicidal agents and their mode of action is not completely elucidated. The results here obtained argue against the oxidative stress hypothesis almost for all the studied compounds, including Nifurtimox. A significant reduction in the level of parasitic low-molecular-weight thiols was observed after Nifurtimox treatment; however, it was not linked to the production of reactive oxidant species. Besides, redox-cycling is only observed at high Nifurtimox concentrations (>400microM), two orders of magnitude higher than the concentration required for anti-proliferative activity (5microM). Our results indicate that an increase in oxidative stress is not the main mechanism of action of Nifurtimox. Among the studied N-oxide-containing heterocycles, benzofuroxan derivatives strongly inhibited parasite dehydrogenase activity and affected mitochondrial membrane potential. The indazole derivative raised intracellular oxidants production, but it was the least effective as anti-T. cruzi.
克氏锥虫病是由锥虫引起的，威胁着南美洲数百万人的生命。与其他被忽视的疾病一样，制药行业几乎没有进行研究和开发工作，治疗依赖于两种药物，即硝呋莫司和苯并硝呋唑，这两种药物是三十多年前经验发现的。硝呋莫司是一种硝基呋喃衍生物，据信通过生物还原硝基基团为硝基阴离子自由基来发挥其生物活性，该自由基与分子氧发生氧化还原循环。虽然有人提出了反对意见，但这一假设已被普遍接受。在本工作中，我们研究了硝呋莫司和五种含 N-氧化物的杂环化合物在克氏锥虫中诱导氧化应激的能力。含 N-氧化物的杂环化合物代表了一类很有前途的新型抗锥虫药物，其作用机制尚未完全阐明。这里获得的结果几乎反对所有研究化合物（包括硝呋莫司）的氧化应激假说。在用硝呋莫司处理后，观察到寄生虫低分子量巯基水平显著降低；然而，这与活性氧化剂的产生无关。此外，只有在高硝呋莫司浓度（>400μM）下才观察到氧化还原循环，这比抗增殖活性所需的浓度（5μM）高两个数量级。我们的结果表明，氧化应激的增加不是硝呋莫司的主要作用机制。在所研究的含 N-氧化物的杂环化合物中，苯并呋咱衍生物强烈抑制寄生虫脱氢酶活性并影响线粒体膜电位。吲唑衍生物增加了细胞内氧化剂的产生，但作为抗 T. cruzi 的效果最差。
