Sarniguet Cynthia, Toloza Jeannette, Cipriani Micaella, Lapier Michel, Vieites Marisol, Toledano-Magaña Yanis, García-Ramos Juan Carlos, Ruiz-Azuara Lena, Moreno Virtudes, Maya Juan Diego, Azar Claudio Olea, Gambino Dinorah, Otero Lucía
Cátedra de Química Inorgánica, DEC, Facultad de Química, Universidad de la República, Gral. Flores 2124, C. C. 1157, 11800, Montevideo, Uruguay.
Biol Trace Elem Res. 2014 Jun;159(1-3):379-92. doi: 10.1007/s12011-014-9964-0. Epub 2014 Apr 17.
Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl2(HL)(HPTA)2]Cl2 with HL=bioactive 5-nitrofuryl containing thiosemicarbazones and PTA=1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl2(HL4)(HPTA)2]Cl2 complex, with HL4=N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC50)=5.2 μM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI)>38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites.
寄生虫病是全球人类疾病和痛苦的主要原因。其中，由原生动物寄生虫溶组织内阿米巴和克氏锥虫引起的阿米巴病和恰加斯病每年导致数千人死亡。缺乏安全有效的化疗方法和/或当前耐药性的出现使得开发用于治疗它们的新型药理学工具变得至关重要。从这个意义上说，在药物无机化学的框架内，金属基药物似乎是找到治疗寄生虫病药理学答案的一个很好的选择。在这项工作中，合成了新型钌配合物[RuCl2(HL)(HPTA)2]Cl2，其中HL =含生物活性5-硝基呋喃基的硫代半卡巴腙，PTA = 1,3,5-三氮杂-7-磷杂金刚烷，并对其进行了全面表征。加入PTA作为共配体以调节配合物的水溶性。事实上，得到的配合物是水溶性的。在体外评估了它们对克氏锥虫和溶组织内阿米巴的活性。[RuCl2(HL4)(HPTA)2]Cl2配合物，其中HL4 = N-苯基-5-硝基呋喃基硫代半卡巴腙，是对两种寄生虫最具活性的化合物。特别是，它对溶组织内阿米巴表现出优异的活性（半数最大抑制浓度(IC50)=5.2 μM），甚至高于参考药物甲硝唑。此外，该配合物对溶组织内阿米巴具有选择性（选择性指数(SI)>38）。所得到的钌配合物的抗寄生虫作用的潜在机制可能涉及对两种寄生虫的氧化应激。此外，配合物可能通过类似插入的模式与DNA相互作用作为第二个潜在靶点。所获得的结果可被视为在寻找对多种寄生虫有活性的金属化合物方面的一项贡献。
