Biosciences and Biotechnology Postgraduate Program, Carlos Chagas Institute, (ICC/Fiocruz/PR), Curitiba, Paraná, Brazil; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil.
Federal University of Rio de Janeiro, Faculty of Pharmacy, Rio de Janeiro, Rio de Janeiro, Brazil; State University of Londrina (UEL/PR), Chemistry Department, Londrina, Paraná, Brazil.
Chem Biol Interact. 2024 Nov 1;403:111216. doi: 10.1016/j.cbi.2024.111216. Epub 2024 Aug 31.
Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania and is responsible for more than 1 million new cases and 70,000 deaths annually worldwide. Treatment has high costs, toxicity, complex and long administration time, several adverse effects, and drug-resistant strains, therefore new therapies are urgently needed. Synthetic compounds have been highlighted in the medicinal chemistry field as a strong option for drug development against different diseases. Organic salts (OS) have multiple biological activities, including activity against protozoa such as Leishmania spp. This study aimed to investigate the in vitro leishmanicidal activity and death mechanisms of a thiohydantoin salt derived from l-arginine (ThS) against Leishmania amazonensis. We observed that ThS treatment inhibited promastigote proliferation, increased ROS production, phosphatidylserine exposure and plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid body accumulation, autophagic vacuole formation, cell cycle alteration, and morphological and ultrastructural changes, showing parasites death. Additionally, ThS presents low cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), and sheep erythrocytes. ThS in vitro cell treatment reduced the percentage of infected macrophages and the number of amastigotes per macrophage by increasing ROS production and reducing TNF-α levels. These results highlight the potential of ThS among thiohydantoins, mainly related to the arginine portion, as a leishmanicidal drug for future drug strategies for leishmaniasis treatment. Notably, in silico investigation of key targets from L. amazonensis, revealed that a ThS compound from the l-arginine amino acid strongly interacts with arginase (ARG) and TNF-α converting enzyme (TACE), suggesting its potential as a Leishmania inhibitor.
利什曼病是一种由利什曼原虫属寄生虫引起的被忽视的热带病，每年在全球导致超过 100 万例新发病例和 7 万人死亡。治疗费用高昂、毒性大、给药复杂且时间长、存在多种不良反应和耐药株，因此急需新的疗法。在药物化学领域，合成化合物已成为针对不同疾病开发药物的强有力选择。有机盐（OS）具有多种生物学活性，包括对原生动物如利什曼原虫属的活性。本研究旨在研究源自 l-精氨酸的硫代乙内酰脲盐（ThS）对利什曼原虫 amazonensis 的体外杀利什曼原虫活性和死亡机制。我们观察到 ThS 处理抑制了前鞭毛体的增殖，增加了 ROS 的产生、磷脂酰丝氨酸的暴露和质膜通透性、线粒体膜电位的丧失、脂滴的积累、自噬泡的形成、细胞周期的改变以及形态和超微结构的变化，表明寄生虫死亡。此外，ThS 在小鼠巨噬细胞（J774A.1）、人单核细胞（THP-1）和绵羊红细胞中表现出低细胞毒性。ThS 在体外细胞处理中通过增加 ROS 的产生和降低 TNF-α 水平，降低了感染巨噬细胞的百分比和每个巨噬细胞中的无鞭毛体数量。这些结果突出了 ThS 在硫代乙内酰脲类药物中的潜力，主要与精氨酸部分有关，作为未来治疗利什曼病的药物策略的杀利什曼原虫药物。值得注意的是，对 L. amazonensis 的关键靶标的计算机研究表明，来自 l-精氨酸的 ThS 化合物与精氨酸酶（ARG）和 TNF-α 转化酶（TACE）强烈相互作用，表明其作为利什曼原虫抑制剂的潜力。
