Toxoplasmosis is a zoonosis that is a worldwide health problem, commonly affecting fetal development and immunodeficient patients. Treatment is carried out with a combination of pyrimethamine and sulfadiazine, which can cause cytopenia and intolerance and does not lead to a parasitological cure of the infection. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins are found in the genome. Previous work showed the hydroxamate-type KDAC inhibitors Tubastatin A (TST) and Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) were effective against . In the present study, the effects of three hydroxamates (, , ), which were originally designed to inhibit human KDAC6, showed different effects against . These compounds contain a heterocyclic cap group and a benzyl linker bearing the hydroxamic acid group in -position. All compounds showed selective activity against proliferation, inhibiting tachyzoite proliferation with IC values in a nanomolar range after 48h treatment. Microscopy analyses showed that after treatment, tachyzoites presented mislocalization of the apicoplast, disorganization of the inner membrane complex, and arrest in the completion of new daughter cells. The number of dividing cells with incomplete endodyogeny increased significantly after treatment, indicating the compounds can interfere in the late steps of cell division. The results obtained in this work that these new hydroxamates should be considered for future tests and the development of new compounds for treating toxoplasmosis.

中文翻译：

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有效的异羟肟酸衍生化合物可抑制弓形虫速殖子的内源性

弓形体病是一种人畜共患病，是一个世界性的健康问题，通常影响胎儿发育和免疫缺陷患者。联合使用乙胺嘧啶和磺胺嘧啶进行治疗，可导致血细胞减少和不耐受，并且不会导致感染的寄生虫治愈。赖氨酸脱乙酰酶 (KDAC) 可从基因组中的组蛋白和非组蛋白的赖氨酸残基中去除乙酰基。先前的工作表明异羟肟酸型 KDAC 抑制剂图巴他汀 A (TST) 和伏立诺他 (Suberoylanilide Hydroxamic Acid, SAHA) 可有效对抗 .在本研究中，最初设计用于抑制人 KDAC6 的三种异羟肟酸盐 (,,) 对 .这些化合物含有杂环封端基团和在-位带有异羟肟酸基团的苄基连接体。所有化合物都表现出选择性的抗增殖活性，处理 48 小时后抑制速殖子增殖，IC 值在纳摩尔范围内。显微镜分析表明，处理后，速殖子出现顶质体错误定位、内膜复合体解体以及新子细胞发育停滞。治疗后，具有不完全内生性的分裂细胞数量显着增加，表明这些化合物可以干扰细胞分裂的后期步骤。这项工作中获得的结果表明，这些新的异羟肟酸盐应考虑用于未来的测试和开发治疗弓形虫病的新化合物。