Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, C/Severo Ochoa s/n, 18071 Granada, Spain.
Instituto de Ciencia Molecular Universidad De Valencia, C/Catedrático José Beltrán 2, 46980 Paterna, Valencia, Spain.
ACS Infect Dis. 2021 Dec 10;7(12):3168-3181. doi: 10.1021/acsinfecdis.1c00215. Epub 2021 Nov 4.
Leishmaniasis is one of the world's most neglected diseases with a worldwide prevalence of 12 million people. There are no effective human vaccines for its prevention, and outdated drugs hamper treatment. Therefore, research aimed at developing new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, here, we present 10 new compounds made up by linking alkylated ethylenediamine units to pyridine or quinoline heterocycles with promising in vitro and in vivo efficacy against promastigote and amastigote forms of , , and species. Three compounds (, , and ) showed a selectivity index much higher in the amastigote form than the reference drug glucantime. These three derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC dose. In addition, these derivatives were substantially more active against the three species tested than glucantime. The mechanism of action of these compounds has been studied, showing alterations in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy due to their effectiveness and their ready synthesis.
利什曼病是世界上最被忽视的疾病之一，全球有 1200 万人患病。目前还没有有效的人类疫苗来预防这种疾病，而且过时的药物也妨碍了治疗。因此，今天研究旨在开发新的治疗工具来对抗利什曼病仍然是一个至关重要的目标。有鉴于此，在这里，我们提出了 10 种由烷基化乙二胺单元与吡啶或喹啉杂环连接而成的新化合物，对前鞭毛体和无鞭毛体形式的 、 、 和 种具有有希望的体外和体内功效。三种化合物（ 、 和 ）在前鞭毛体形式下的选择性指数明显高于参考药物葡萄糖酸锑。这三种衍生物影响寄生虫感染率；结果是寄生虫感染率低于用 IC 剂量测试的葡萄糖酸锑。此外，这些衍生物对三种测试的 种的活性明显高于葡萄糖酸锑。这些化合物的作用机制已经研究过，显示葡萄糖代谢的改变，并导致铁超氧化物歧化酶抑制水平更高。由于这些化合物的有效性和易于合成，它们可能成为治疗利什曼病的潜在候选药物。
