Laboratorio de Biocatálisis. Departamento de Química Orgánica y UMYMFOR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, piso 3, C1428EGA Buenos Aires, Argentina.
Centro de Investigaciones sobre Porfirias y Porfirinas (CIPYP, UBA-CONICET), Hospital de Clínicas José de San Martín, Avenida Córdoba 2351, 1120 Buenos Aires, Argentina.
Bioorg Chem. 2019 Mar;83:526-534. doi: 10.1016/j.bioorg.2018.10.053. Epub 2018 Oct 31.
As a part of our project aimed at developing new safe chemotherapeutic agents against tropical diseases, a series of aryl derivatives of 2- and 3-aminoquinoline, some of them new compounds, was designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for American trypanosomiasis (Chagas' disease), and Leishmania mexicana, the etiological agent of Leishmaniasis. Some of them showed a remarkable activity as parasite growth inhibitors. Fluorine-containing derivatives 11b and 11c were more than twice more potent than geneticin against intracellular promastigote form of Leishmania mexicana exhibiting both IC values of 41.9 μM. The IC values corresponding to fluorine and chlorine derivatives 11b-d were in the same order than benznidazole against epimastigote form. These drugs are interesting examples of effective antiparasitic agents with outstanding potential not only as lead drugs but also to be used for further in vivo studies. In addition, the obtained compounds showed no toxicity in Vero cells, which makes them good candidates to control tropical diseases. Regarding the probable mode of action, assayed quinoline derivatives interacted with hemin, inhibiting its degradation and generating oxidative stress that is not counteracted by the antioxidant defense system of the parasite.
作为我们开发针对热带疾病的新型安全化疗药物项目的一部分，我们设计、合成并评估了一系列芳基 2-和 3-氨基喹啉衍生物，其中一些是新化合物，作为抗寄生虫药物对引起美洲锥虫病（恰加斯病）的寄生虫 Trypanosoma cruzi 和引起利什曼病的病原体 Leishmania mexicana 的增殖抑制剂。其中一些表现出显著的活性。含氟衍生物 11b 和 11c 对 Leishmania mexicana 的细胞内前鞭毛体的抑制活性比遗传霉素强两倍以上，IC 值分别为 41.9 μM。氟和氯衍生物 11b-d 的 IC 值与苯并硝唑对滋养体形式的抑制活性相当。这些药物是有效抗寄生虫药物的有趣示例，不仅具有作为先导药物的巨大潜力，而且可用于进一步的体内研究。此外，获得的化合物在 Vero 细胞中没有显示出毒性，这使它们成为控制热带疾病的良好候选药物。关于可能的作用模式，测定的喹啉衍生物与血红素相互作用，抑制其降解并产生氧化应激，而寄生虫的抗氧化防御系统无法抵消这种应激。
