Leishmaniasis is a widespread tropical infection caused by different species of Leishmania protozoa. Many of the available drugs against the disease are toxic and in certain cases parasite drug resistance is developed. The discovery of drugs for the treatment of leishmaniasis is a pressing concern. In the present work, we describe in vitro studies of the phenolic compound methyl gallate (MG) against Leishmania (Leishmania) amazonensis and its possible mechanisms of action. The in vitro activity of MG was assayed against L. amazonensis (promastigotes, axenic amastigotes, and intramacrophagic amastigotes). Cytotoxicity tests were performed with J774A.1 macrophages and THP-1 cell derived macrophages. To evaluate mechanisms of action, we analyzed cellular TNF-α, IL-12, IFN-γ, IL-10, IL-6, NO, ROS levels, arginase activity, and structural mechanisms (phagocytic and lysosomal activities) involving macrophage activation. Meglumine antimoniate and amphotericin B were used as reference drugs. It was observed that MG effectively inhibited the growth of both promastigote (IC50 5.71 μM) and amastigote-like forms (EC50 5.39 μM), with much higher selectivity indexes than the reference drugs, being more benign towards J774A.1 macrophages than meglumine antimoniate and amphotericin B, at 1631- and 70.92-fold respectively, with respect to the promastigote form. Additionally, MG proved to be even more active against intracellular amastigotes of the parasite (EC50 4.24 μM). Our results showed that antileishmania activity was associated with increased TNF-α, IL-12, NO and ROS levels, as well as decreased IL-6 and decreased arginase activity. In addition, MG induced increased phagocytic capability, and lysosomal volume in macrophages; structural parameters of microbicidal activity. Taken together, our results suggest that MG may be a promising candidate for new drug development against leishmaniasis.

中文翻译：

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没食子酸甲酯：选择性抗疟疾活性与宿主细胞定向作用有关。

利什曼病是由不同种类的利什曼原虫引起的广泛的热带感染。许多可用于治疗该疾病的药物都是有毒的，在某些情况下会产生寄生虫耐药性。寻找用于治疗利什曼病的药物是紧迫的问题。在本工作中，我们描述了酚类化合物没食子酸甲酯（MG）对抗利什曼原虫（Leishmania）amazonensis的体外研究及其可能的作用机理。测定了MG的体外活性，以针对亚马逊乳杆菌（前鞭毛体，轴突性阿马鞭毛虫和巨噬细胞内的阿马鞭毛虫）。用J774A.1巨噬细胞和THP-1细胞衍生的巨噬细胞进行细胞毒性试验。为了评估其作用机理，我们分析了细胞中的TNF-α，IL-12，IFN-γ，IL-10，IL-6，NO，ROS水平，精氨酸酶活性，以及涉及巨噬细胞活化的结构机制（吞噬和溶酶体活性）。葡甲胺锑酸盐和两性霉素B用作参考药物。观察到，MG有效地抑制了前鞭毛体（IC50 5.71μM）和类似鞭毛体的形式（EC50 5.39μM）的生长，选择性指数比参比药物高得多，对J774A.1巨噬细胞的敏感性比葡甲胺锑酸盐和葡甲胺盐更为明显。两性霉素B相对于前鞭毛体形式分别为1631和70.92倍。另外，事实证明，MG对寄生虫的胞内变形虫具有更强的活性（EC50 4.24μM）。我们的结果表明，抗躁狂症活动与TNF-α，IL-12，NO和ROS水平升高以及IL-6降低和精氨酸酶活性降低有关。此外，MG诱导巨噬细胞吞噬能力和溶酶体体积增加；杀菌活性的结构参数。综上所述，我们的结果表明MG可能是抗利什曼病的新药开发的有希望的候选者。