Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, 36036-900, Juiz de Fora, Minas Gerais, Brazil.
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora, 36036-900, Juiz de Fora, Minas Gerais, Brazil.
Biomed Pharmacother. 2018 Oct;106:1082-1090. doi: 10.1016/j.biopha.2018.07.056. Epub 2018 Jul 17.
The search for new drugs for the treatment of leishmaniasis is an important strategy for improving the current therapeutic arsenal for the disease. There are several limitations to the available drugs including high toxicity, low efficacy, prolonged parenteral administration, and high costs. Steroids are a diverse group of compounds with various applications in pharmacology. However, the antileishmanial activity of this class of molecules has not yet been explored. Therefore, in the present study, we investigated the antileishmanial activity and cytotoxicity of novel steroids against murine macrophages with a focus on the derivatives of cholesterol (CD), cholic acid (CA), and deoxycholic acid (DA). Furthermore, the mechanism of action of the best compound was assessed, and in silico studies to evaluate the physicochemical and pharmacokinetic properties were also conducted. Among the sixteen derivatives, schiffbase2, CD2 and deoxycholic acid derivatives (DOCADs) were effective against promastigotes of Leishmania species. Despite their low toxicity to macrophages, the majority of DOCADs were active against intracellular amastigotes of L. amazonensis, and DOCAD5 exhibited the best biological effect against these parasitic stages (IC = 15.34 μM). Neither the CA derivatives (CAD) nor DA alone inhibited the intracellular parasites. Thus, the absence of hydroxyl in the C-7 position of the steroid nucleus, as well as the modification of the acid group in DOCADs were considered important for antileishmanial activity. The treatment of L. amazonensis promastigote forms with DOCAD5 induced biochemical changes such as depolarization of the mitochondrial membrane potential, increased ROS production and cell cycle arrest. No alterations in parasite plasma membrane integrity were observed. In silico physicochemical and pharmacokinetic studies suggest that DOCAD5 could be a good candidate for an oral drug. The data demonstrate the potential antileishmanial effect of certain steroid derivatives and encourage new in vivo studies.
寻找治疗利什曼病的新药是改善该疾病现有治疗方法的重要策略。现有的药物存在多种局限性，包括毒性高、疗效低、需要长期注射以及成本高。甾体是一类具有多种药理学应用的化合物。然而，这类分子的抗利什曼活性尚未得到探索。因此，在本研究中，我们研究了新型甾体对小鼠巨噬细胞的抗利什曼活性和细胞毒性，重点研究了胆固醇（CD）、胆酸（CA）和脱氧胆酸（DA）的衍生物。此外，还评估了最佳化合物的作用机制，并进行了计算化学研究以评估其物理化学和药代动力学特性。在所研究的 16 种衍生物中，席夫碱 2、CD2 和脱氧胆酸衍生物（DOCADs）对利什曼原虫的前鞭毛体有效。尽管它们对巨噬细胞的毒性较低，但大多数 DOCADs 对 L. amazonensis 的细胞内无鞭毛体有效，DOCAD5 对这些寄生虫阶段的生物活性最好（IC = 15.34 μM）。CA 衍生物（CAD）和单独的 DA 均不能抑制细胞内寄生虫。因此，甾体核 C-7 位无羟基以及 DOCADs 中酸基团的修饰被认为对抗利什曼活性很重要。DOCAD5 处理 L. amazonensis 前鞭毛体形式可诱导生化变化，如线粒体膜电位去极化、ROS 产生增加和细胞周期停滞。未观察到寄生虫质膜完整性的改变。计算化学物理化学和药代动力学研究表明，DOCAD5 可能是口服药物的良好候选物。这些数据表明某些甾体衍生物具有潜在的抗利什曼活性，并鼓励进行新的体内研究。
