Instituto de Química, Universidade Federal de Uberlândia, Av. João Naves de Ávila, 2121, Uberlândia, MG, 38408-100, Brazil.
Instituto de Genética e Bioquímica, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil.
Biometals. 2018 Dec;31(6):1003-1017. doi: 10.1007/s10534-018-0145-z. Epub 2018 Oct 4.
Leishmaniasis, a neglected tropical disease caused by protozoans of the genus Leishmania, kills around 20-30 thousand people in Africa, Asia, and Latin America annually and, despite its potential lethality, it can be treated and eventually cured. However, the current treatments are limited owing to severe side effects and resistance development by some Leishmania. These factors make it urgent to develop new leishmanicidal drugs. In the present study, three ruthenium(II) organometallic complexes containing as ligands the commercially available anti-inflammatories diclofenac (dic), ibuprofen (ibu), and naproxen (nap) were synthesized, characterized, and subjected to in vitro leishmanicidal activity. The in vitro cytotoxicity assays against Leishmania (L.) amazonensis and Leishmania (L.) infantum promastigotes have shown that complexes [RuCl(dic)(η-p-cymene)] (1) and [RuCl(nap)(η-p-cymene)] (3) were active against both Leishmania species. Complex [RuCl(ibu)(η-p-cymene)] (2) has exhibited no activity. The IC values for the two active complexes were respectively 7.42 and 23.55 μM, for L. (L.) amazonensis, and 8.57 and 42.25 μM, for L. (L.) infantum. Based on the toxicological results and computational analysis, we proposed a correlation between the complexes and their activity. Our results suggest both complexation to ruthenium(II) and ligands structure are key elements to leishmanicidal activity.
利什曼病是一种由利什曼原虫属原生动物引起的被忽视的热带病，每年在非洲、亚洲和拉丁美洲导致约 2 万至 3 万人死亡，尽管它具有潜在的致命性，但可以治疗并最终治愈。然而，由于一些利什曼原虫的严重副作用和耐药性的发展，目前的治疗方法受到限制。这些因素使得开发新的杀利什曼原虫药物变得紧迫。在本研究中，合成了三种含有市售抗炎药双氯芬酸（dic）、布洛芬（ibu）和萘普生（nap）作为配体的钌（II）有机金属配合物，并对其进行了体外杀利什曼原虫活性研究。体外细胞毒性试验表明，配合物[RuCl（dic）（η-p-cymene）]（1）和[RuCl（nap）（η-p-cymene）]（3）对两种利什曼原虫均具有活性。配合物[RuCl（ibu）（η-p-cymene）]（2）没有活性。两种活性配合物对 L.（L.）亚马逊和 L.（L.）婴儿前鞭毛体的 IC 值分别为 7.42 和 23.55 μM，8.57 和 42.25 μM。基于毒理学结果和计算分析，我们提出了配合物与其活性之间的相关性。我们的结果表明，配合物的络合和配体结构是杀利什曼原虫活性的关键因素。
