Programa de Pós-Graduação Em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena, 190, Santa Efigênia, 30130-100, Belo Horizonte, Minas Gerais, Brazil.
Grupo de Síntese e Pesquisa de Compostos Bioativos, Departamento de Química, Universidade Federal de Viçosa, Avenida PH Rolfs S/N, 36570-900, Viçosa, Minas Gerais, Brazil.
Exp Parasitol. 2023 Aug;251:108555. doi: 10.1016/j.exppara.2023.108555. Epub 2023 May 27.
The treatment against leishmaniasis presents problems, mainly due to their toxicity of the drugs, high cost and/or by the emergence of parasite resistant strains. In this context, new therapeutics should be searched. In this study, two novel synthetic derivatives from vanillin: [4-(2-hydroxy-3-(4-octyl-1H-1,2,3-triazol-1-yl)propoxy)-3-methoxybenzaldehyde] or 3s and [4-(3-(4-decyl-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)-3-methoxybenzaldehyde] or 3t, were evaluated regarding their antileishmanial activity against distinct parasite species able to cause cutaneous and visceral leishmaniasis. Results showed that compounds 3s and 3t were effective against Leishmania infantum, L. amazonensis and L. braziliensis promastigote and amastigote-like forms, showing selectivity index (SI) of 25.1, 18.2 and 22.9, respectively, when 3s was used against promastigotes, and of 45.2, 7.5 and 15.0, respectively, against amastigote-like stage. Using the compound 3t, SI values were 45.2, 53.0 and 80.0, respectively, against promastigotes, and of 35.9, 46.0 and 58.4, respectively, against amastigote-like forms. Amphotericin B (AmpB) showed SI values of 5.0, 7.5 and 15.0, respectively, against promastigotes, and of 3.8, 5.0 and 7.5, respectively, against amastigote-like stage. The treatment of infected macrophages and inhibition of the infection upon pre-incubation with the molecules showed that they were effective in reducing the infection degree and inhibiting the infection in pre-incubated parasites, respectively, as compared to data obtained using AmpB. The mechanism of action of 3s and 3t was evaluated in L. infantum, revealing that both 3s and 3t altered the parasite mitochondrial membrane potential leading to reactive oxygen species production, increase in lipid corps and changes in the cell cycle, causing the parasite' death. A preliminary assay using the cell culture supernatant from treated and infected macrophages showed that 3s and 3t induced higher IL-12 and lower IL-10 values; suggesting the development of an in vitro Th1-type response in the treated cells. In this context, data indicated that 3s and 3t could be considered therapeutic agents to be tested in future studies against leishmaniasis.
抗利什曼病的治疗存在问题，主要是由于药物的毒性、高成本和/或寄生虫耐药株的出现。在这种情况下，应该寻找新的治疗方法。在这项研究中，对香草醛的两种新型合成衍生物[4-(2-羟基-3-(4-辛基-1H-1,2,3-三唑-1-基)丙氧基)-3-甲氧基苯甲醛]或 3s 和[4-(3-(4-癸基-1H-1,2,3-三唑-1-基)-2-羟基丙氧基)-3-甲氧基苯甲醛]或 3t 进行了评估，以研究它们对不同种寄生虫的抗利什曼病活性，这些寄生虫能够引起皮肤利什曼病和内脏利什曼病。结果表明，化合物 3s 和 3t 对利什曼原虫、L. amazonensis 和 L. braziliensis 前鞭毛体和无鞭毛体样形式有效，当 3s 用于前鞭毛体时，其选择性指数（SI）分别为 25.1、18.2 和 22.9，而当用于无鞭毛体样阶段时，SI 分别为 45.2、7.5 和 15.0。使用化合物 3t 时，对前鞭毛体的 SI 值分别为 45.2、53.0 和 80.0，对无鞭毛体样形式的 SI 值分别为 35.9、46.0 和 58.4。两性霉素 B（AmpB）对前鞭毛体的 SI 值分别为 5.0、7.5 和 15.0，对无鞭毛体样形式的 SI 值分别为 3.8、5.0 和 7.5。用感染的巨噬细胞进行治疗和用分子进行预孵育以抑制感染，结果表明，与使用 AmpB 获得的数据相比，它们在降低感染程度和抑制预孵育寄生虫感染方面均有效。在 L. infantum 中评估了 3s 和 3t 的作用机制，结果表明，3s 和 3t 均改变了寄生虫的线粒体膜电位，导致活性氧的产生、脂体的增加和细胞周期的变化，导致寄生虫死亡。用处理和感染的巨噬细胞的细胞培养上清液进行的初步检测表明，3s 和 3t 诱导更高的 IL-12 和更低的 IL-10 值；这表明在处理细胞中产生了体外 Th1 型反应。在这种情况下，数据表明 3s 和 3t 可以被认为是治疗药物，将在未来的利什曼病研究中进行测试。
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