UFMA-Federal University of Maranhão, Center for Exact Sciences and Technology (CCET), Post Graduate Program in Chemistry, São Luís CEP 65080-805, Brazil.
UNESP, São Paulo State University Júlio de Mesquita Filho, Institute of Chemistry, Post Graduate Program in Chemistry, Araraquara CEP 14800-060, Brazil.
Mol Biochem Parasitol. 2024 Sep;259:111629. doi: 10.1016/j.molbiopara.2024.111629. Epub 2024 May 13.
Leishmaniases comprise a group of infectious parasitic diseases caused by various species of Leishmania and are considered a significant public health problem worldwide. Only a few medications, including miltefosine, amphotericin B, and meglumine antimonate, are used in current therapy. These medications are associated with severe side effects, low efficacy, high cost, and the need for hospital support. Additionally, there have been occurrences of drug resistance. Additionally, only a limited number of drugs, such as meglumine antimonate, amphotericin B, and miltefosine, are available, all of which are associated with severe side effects. In this context, the need for new effective drugs with fewer adverse effects is evident. Therefore, this study investigated the anti-Leishmania activity of a dichloromethane fraction (DCMF) extracted from Arrabidaea brachypoda roots. This fraction inhibited the viability of L. infantum, L. braziliensis, and L. Mexicana promastigotes, with IC values of 10.13, 11.44, and 11.16 µg/mL, respectively, and against L. infantum amastigotes (IC = 4.81 µg/mL). Moreover, the DCMF exhibited moderate cytotoxicity (CC = 25.15) towards RAW264.7 macrophages, with a selectivity index (SI) of 5.2. Notably, the DCMF caused damage to the macrophage genome only at 40 µg/mL, which is greater than the IC found for all Leishmania species. The results suggest that DCMF demonstrates similar antileishmanial effectiveness to isolated brachydin B, without causing genotoxic effects on mammalian cells. This finding is crucial because the isolation of the compounds relies on several steps and is very costly while obtaining the DCMF fraction is a simple and cost-effective process. Furthermore, In addition, the potential mechanisms of action of brachydins were also investigated. The computational analysis indicates that brachydin compounds bind to the Triosephosphate isomerase (TIM) enzyme via two main mechanisms: destabilizing the interface between the homodimers and interacting with catalytic residues situated at the site of binding. Based on all the results, DCMF exhibits promise as a therapeutic agent for leishmaniasis due to its significantly reduced toxicity in comparison to the adverse effects associated with current reference treatments.
利什曼病是一组由各种利什曼原虫引起的传染性寄生虫病，被认为是全球范围内的一个重大公共卫生问题。目前的治疗方法仅使用几种药物，包括米替福新、两性霉素 B 和葡萄糖酸锑钠。这些药物存在严重的副作用、疗效低、成本高和需要医院支持等问题。此外，还存在药物耐药性的情况。此外，目前可用的药物数量有限，例如葡萄糖酸锑钠、两性霉素 B 和米替福新，所有这些药物都有严重的副作用。在这种情况下，显然需要具有较少不良反应的新的有效药物。因此，本研究调查了从 Arrabidaea brachypoda 根中提取的二氯甲烷部分 (DCMF) 的抗利什曼原虫活性。该部分抑制了 L. infantum、L. braziliensis 和 L. Mexicana 前鞭毛体的活力，IC 值分别为 10.13、11.44 和 11.16μg/ml，对 L. infantum 无鞭毛体的 IC 值为 4.81μg/ml。此外，DCMF 对 RAW264.7 巨噬细胞表现出中等的细胞毒性（CC = 25.15），其选择性指数（SI）为 5.2。值得注意的是，DCMF 仅在 40μg/ml 时对巨噬细胞基因组造成损害，这大于所有利什曼原虫种的 IC 值。结果表明，DCMF 表现出与分离的 brachydin B 相似的抗利什曼原虫效果，而不会对哺乳动物细胞造成遗传毒性。这一发现至关重要，因为化合物的分离依赖于多个步骤，成本非常高，而获得 DCMF 部分是一个简单且具有成本效益的过程。此外，还研究了 brachydin 化合物的潜在作用机制。计算分析表明，brachydin 化合物通过两种主要机制与三磷酸甘油异构酶（TIM）酶结合：破坏同源二聚体之间的界面和与结合部位的催化残基相互作用。基于所有结果，DCMF 由于其毒性明显低于当前参考治疗方法相关的副作用，因此有望成为治疗利什曼病的药物。
