Ramírez-Macías Inmaculada, Marín Clotilde, Es-Samti Hakima, Fernández Antonio, Guardia Juan José, Zentar Huda, Agil Ahmad, Chahboun Rachid, Alvarez-Manzaneda Enrique, Sánchez-Moreno Manuel
Department of Parasitology. University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
Parasitol Int. 2012 Sep;61(3):405-13. doi: 10.1016/j.parint.2012.02.001. Epub 2012 Feb 16.
The in vitro leishmanicidal (Leishmania infantum and Leishmania braziliensis) and trypanocidal (Trypanosoma cruzi) activities of different compounds were evaluated. These compounds, of vegetal origin but synthesised in our laboratory, included five taiwaniaquinoid derivatives (S-567; S-569; S-589; S-602 and A-246) and one abietane quinone (P-1). The in vitro activity of the compounds on extracellular and intracellular forms of the two Leishmania species and T. cruzi was assayed. Infectivity and cytotoxicity tests for the Leishmania species were conducted on J774.2 macrophage cells using Glucantime as the reference drug. From all the compounds assayed, the derivatives P-1>S-567 were more active and less toxic than Glucantime. Infection rates and amastigote means indicated that these two compounds were the most active in both Leishmania species. In the case of T. cruzi, the best derivatives were P-1 and S-567, at the same levels as for the Leishmania species. These compounds exhibited the most potent anti-proliferative activity against the extracellular vector form (the epimastigote), the extracellular host form (the trypomastigote), and the intracellular host form (the amastigote), with lower toxicity than that of the reference drug Benznidazole. Metabolite excretion studies showed that alterations mainly at the level of the mitochondria may explain observed metabolic changes in succinate and acetate production, perhaps due to the disturbance of enzymes involved in sugar metabolism within the mitochondrion. The in vivo studies for T. cruzi provided results consistent with those found in vitro. No signs of toxicity were detected in mice treated with the compounds tested, and the parasitic charge was slightly lower than in the control. The effects of these two compounds were also demonstrated with the change in the anti-T. cruzi antibody levels during the chronic stage.
评估了不同化合物的体外杀利什曼原虫（婴儿利什曼原虫和巴西利什曼原虫）及杀锥虫（克氏锥虫）活性。这些化合物源自植物，但在我们实验室合成，包括五种台湾杉醌衍生物（S - 567；S - 569；S - 589；S - 602和A - 246）和一种枞酸型醌（P - 1）。测定了这些化合物对两种利什曼原虫和克氏锥虫细胞外及细胞内形式的体外活性。以葡糖胺锑钠作为参比药物，在J774.2巨噬细胞上对利什曼原虫进行感染性和细胞毒性试验。在所测定的所有化合物中，衍生物P - 1 > S - 567比葡糖胺锑钠活性更高且毒性更低。感染率和无鞭毛体平均数表明这两种化合物对两种利什曼原虫均最具活性。对于克氏锥虫，最佳衍生物是P - 1和S - 567，与利什曼原虫的情况处于相同水平。这些化合物对细胞外媒介形式（前鞭毛体）、细胞外宿主形式（锥鞭毛体）和细胞内宿主形式（无鞭毛体）表现出最有效的抗增殖活性，且毒性低于参比药物苯硝唑。代谢物排泄研究表明，主要在线粒体水平的改变可能解释了所观察到的琥珀酸和乙酸产生的代谢变化，这可能是由于线粒体中参与糖代谢的酶受到干扰所致。对克氏锥虫的体内研究结果与体外研究结果一致。在用测试化合物处理的小鼠中未检测到毒性迹象，且寄生虫负荷略低于对照组。这两种化合物还通过慢性期抗克氏锥虫抗体水平的变化得到了验证。
