Laboratory of Pathology of Infectious Diseases (LIM50), Department of Pathology, Medical School of São Paulo University, Av. Dr. Arnaldo, 455, Cerqueira César, São Paulo 01246-903, SP, Brazil.
Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, 09210-180 São Paulo, Brazil.
Bioorg Chem. 2020 Sep;102:104056. doi: 10.1016/j.bioorg.2020.104056. Epub 2020 Jul 2.
Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. The treatment of all forms of leishmaniasis relies on first-line drug, pentavalent antimonial, and in cases of drug failure, the second-line drug amphotericin B has been used. Besides the high toxicity of drugs, parasites can be resistant to antimonial in some areas of the World, making it necessary to perform further studies for the characterization of new antileishmanial agents. Thus, the aim of the present work was to evaluate the leishmanicidal activity of tolnaftate, a selective reversible and non-competitive inhibitor of the fungal enzyme squalene epoxidase, which is involved in the biosynthesis of ergosterol, essential to maintain membrane physiology in fungi as well as trypanosomatids. Tolnaftate eliminated promastigote forms of L. (L.) amazonensis, L. (V.) braziliensis and L. (L.) infantum (EC ~ 10 μg/mL and SI ~ 20 for all leishmanial species), and intracellular amastigote forms of all studied species (EC ~ 23 μg/mL in infections caused by dermatotropic species; and 11.7 μg/mL in infection caused by viscerotropic species) with high selectivity toward parasites [SI ~ 8 in infections caused by dermatotropic species and 17.4 for viscerotropic specie]. Promastigote forms of L. (L.) amazonensis treated with the EC of tolnaftate displayed morphological and physiological changes in the mitochondria and cell membrane. Additionally, promastigote forms treated with tolnaftate EC reduced the level of ergosterol by 5.6 times in comparison to the control parasites. Altogether, these results suggest that tolnaftate has leishmanicidal activity towards Leishmania sp., is selective, affects the cell membrane and mitochondria of parasites and, moreover, inhibits ergosterol production in L. (L.) amazonensis.
利什曼病是一种由利什曼原虫属的原生动物寄生虫引起的传染病。所有形式的利什曼病的治疗都依赖于一线药物五价锑，并且在药物失效的情况下，已经使用了二线药物两性霉素 B。除了药物的高毒性外，寄生虫在世界上的某些地区可能对锑产生耐药性，因此有必要进一步研究新的抗利什曼原虫药物。因此，本工作的目的是评估托萘酯的杀利什曼原虫活性，托萘酯是一种真菌 squalene epoxidase 的选择性可逆和非竞争性抑制剂，该酶参与麦角固醇的生物合成，麦角固醇是维持真菌以及锥虫生物膜生理学所必需的。托萘酯消除了 L.（L.）亚马逊ensis、L.（V.）braziliensis 和 L.（L.）infantum 的前鞭毛体形式（对所有利什曼原虫物种的 EC ~ 10μg/mL 和 SI ~ 20），以及所有研究物种的内体无鞭毛体形式（对皮肤利什曼原虫引起的感染的 EC ~ 23μg/mL；对内脏利什曼原虫引起的感染的 EC ~ 11.7μg/mL），对寄生虫具有高选择性 [对皮肤利什曼原虫引起的感染的 SI ~ 8，对内脏利什曼原虫引起的感染的 SI ~ 17.4]。用托萘酯 EC 处理的 L.（L.）亚马逊ensis 前鞭毛体表现出线粒体和细胞膜的形态和生理变化。此外，用托萘酯 EC 处理的前鞭毛体与对照寄生虫相比，麦角固醇水平降低了 5.6 倍。总之，这些结果表明托萘酯对利什曼原虫具有杀利什曼原虫活性，具有选择性，影响寄生虫的细胞膜和线粒体，并且抑制 L.（L.）亚马逊ensis 中的麦角固醇生成。
