Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires (Argentina).
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA, 30602 (USA).
ChemMedChem. 2015 Jun;10(6):1094-108. doi: 10.1002/cmdc.201500100. Epub 2015 Apr 27.
As a part of our project aimed at searching for new safe chemotherapeutic agents against parasitic diseases, several compounds structurally related to the antiparasitic agent WC-9 (4-phenoxyphenoxyethyl thiocyanate), which were modified at the terminal phenyl ring, were designed, synthesized, and evaluated as growth inhibitors against Trypanosoma cruzi, the etiological agent of Chagas disease, and Toxoplasma gondii, the parasite responsible of toxoplasmosis. Most of the synthetic analogues exhibited similar antiparasitic activity and were slightly more potent than our lead WC-9. For example, two trifluoromethylated derivatives exhibited ED50 values of 10.0 and 9.2 μM against intracellular T. cruzi, whereas they showed potent action against tachyzoites of T. gondii (ED50 values of 1.6 and 1.9 μM against T. gondii). In addition, analogues of WC-9 in which the terminal aryl group is in the meta position with respect to the alkyl chain bearing the thiocyanate group showed potent inhibitory action against both T. cruzi and T. gondii at the very low micromolar range, which suggests that a para-phenyl substitution pattern is not necessary for biological activity.
作为我们寻找新型安全抗寄生虫药物的项目的一部分，我们设计、合成并评估了几种结构上与抗寄生虫药物 WC-9（4-苯氧基苯氧基乙基硫氰酸酯）相关的化合物，这些化合物在末端苯环上进行了修饰，以作为生长抑制剂针对引起恰加斯病的寄生虫克氏锥虫和引起弓形体病的寄生虫弓形体。大多数合成类似物表现出相似的抗寄生虫活性，并且比我们的先导化合物 WC-9 略强。例如，两个三氟甲基化衍生物对细胞内的克氏锥虫表现出 ED50 值为 10.0 和 9.2 μM，而对刚地弓形虫的速殖子则表现出强烈的作用（对刚地弓形虫的 ED50 值分别为 1.6 和 1.9 μM）。此外，在末端芳基相对于带有硫氰酸酯基团的烷基链处于间位的 WC-9 类似物对克氏锥虫和刚地弓形虫均表现出强烈的抑制作用，其抑制作用在非常低的微摩尔范围内，这表明对生物活性而言，对位取代模式并非必需。
