利什曼酶包括一组由各种利什曼原虫引起的感染性寄生虫病,并且被认为是世界范围内的重大公共卫生问题。目前的疗法面临严重的局限性,包括低功效,高成本,以及需要医院支持并且已经表现出抵抗力的管理途径。此外,只有有限数量的药物,如锑酸葡甲胺,两性霉素B,和米替福辛,可用,所有这些都与严重的副作用有关。在这种情况下,显然需要新的有效药物,副作用更少。因此,这项研究调查了从Arrabidaea短poda根中提取的二氯甲烷级分(DCMF)的抗利什曼原虫活性。该部分抑制了L.infantum的生存力,L.巴西,和L.Mexicana长鼻肌,IC50值为10.13、11.44和11.16µg/mL,分别,和针对婴儿羊毛虫(IC50=4.81µg/mL)。此外,DCMF对RAW264.7巨噬细胞表现出中等的细胞毒性(CC50=25.15),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,大于所有利什曼原虫物种的IC50。还研究了短肽的潜在作用机制。结果表明,DCMF表现出与分离的短齿素B相似的抗利什曼原虫功效,不会对哺乳动物细胞产生基因毒性作用。该发现是至关重要的,因为化合物的分离依赖于几个步骤并且非常昂贵,而获得DCMF级分是简单且成本有效的方法。此外,计算分析表明,短生素化合物通过两种主要机制与磷酸三糖异构酶(TIM)结合:使同二聚体之间的界面不稳定以及与位于结合位点的催化残基相互作用。基于所有的结果,DCMF表现出作为利什曼病的治疗剂的希望,因为与与当前参考治疗相关的不良反应相比,其毒性显著降低。
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 IC50 values of 10.13, 11.44, and 11.16 µg/mL, respectively, and against L. infantum amastigotes (IC50 = 4.81 µg/mL). Moreover, the DCMF exhibited moderate cytotoxicity (CC50 = 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 IC50 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.