Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, 1210 Vienna, Austria.
Pharmacy Department, Institute of Pharmacy and Food Sciences, University of Havana, Havana 13600, Cuba.
Molecules. 2022 Oct 13;27(20):6846. doi: 10.3390/molecules27206846.
Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogPOW larger than 3.5 and a polar surface area smaller than 100 Å2. The most effective compounds (IC50 in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.
利什曼病是一种由原生动物利什曼原虫寄生虫引起的虫媒病。以前的研究表明，内过氧化物（EP）可以选择性地杀死宿主细胞中的利什曼原虫。因此，我们在利什曼原虫 tarentolae 前体（LtP）和 J774 巨噬细胞的模型系统中研究了一组新的蒽衍生 EP（AcEP）及其非内过氧化物类似物，以研究它们的抗利什曼原虫活性和选择性。通过研究它们在化学系统和利什曼原虫中的铁（II）反应，探讨了有效化合物的作用机制。结构参数与活性的相关性表明，在该化合物集中，活性化合物的 LogPOW 大于 3.5，极性表面积小于 100 Å2。具有最高选择性（SI > 30）的最有效化合物（LtP 中的 IC50 < 2 µM）是吡啶基-/叔丁基取代的 AcEP。有趣的是，它们的类似物也表现出活性和选择性。在机制研究中，表明 EP 在化学系统中和 LtP 中由于其 EP 基团而被铁激活。然而，EP 基团之外的分子结构对它们在利什曼原虫中的差异线粒体抑制有显著贡献。鉴定的化合物对是随后在体外致病性利什曼原虫和动物模型中进行实验的良好起点。
