Leishmaniases are infectious diseases, caused by protozoa of the Leishmania genus. These drugs present high toxicity, long-term administration, many adverse effects and are expensive, besides the identification of resistant parasites. In this work, the antileishmanial activity of quinoline derivative salts (QDS) was evaluated, as well as the toxicity on mammalian cells and the mechanism of action of the most promising compound. Among the compound tested, only the compound QDS3 showed activity against promastigotes and amastigotes of Leishmania spp., being more active against the intracellular amastigotes of L. amazonensis-GFP (IC₅₀ of 5.48 μM). This value is very close to the one observed for miltefosine (IC₅₀ of 4.05 μM), used as control drug. Furthermore, the compound QDS3 exhibited a selective effect, being 40.35 times more toxic to the amastigote form than to the host cell. Additionally, promastigotes of L. amazonensis treated with this compound exhibited characteristics of cells in the process of apoptosis such as mitochondrial membrane depolarization, mitochondrial swelling, increase of ROS production, phosphatidylserine externalization, reduced and rounded shape, and cell cycle alteration. The integrity of the plasma membrane remained unaltered, excluding necrosis in treated promastigotes. The compound QDS3 inhibited the formation of autophagic vacuoles, which may have contributed to parasite death by preventing autophagic mechanisms in the removal of damaged organelles, intensifying the damage caused by the treatment, highlighting the antileishmanial effect of this compound. In addition, treatment with QDS3 induced increased ROS levels in L. amazonensis-infected macrophages, but not in uninfected host cell. These data reinforce that the induction of oxidative stress is one of the main toxic effects caused by the treatment with the compound QDS3 in L. amazonensis, causing irreversible damage and triggering a selective death of intracellular parasites. Data shown here confirm the biological activity of quinoline derivatives and encourage future in vivo studies with this compound in the murine model.

利什曼病是由利什曼原虫属的原生动物引起的感染性疾病。这些药物除了鉴定出抗药性寄生虫外，还显示出高毒性，长期给药，许多不良反应且价格昂贵。在这项工作中，评估了喹啉衍生物盐（QDS）的抗衰老活性，以及对哺乳动物细胞的毒性和最有希望的化合物的作用机理。在所测试的化合物中，仅化合物QDS3对利什曼原虫的前鞭毛体和变形虫具有活性，对亚马逊乳杆菌-GFP的胞内变形虫具有更强的活性（IC ₅₀5.48μM）。该值非常接近于用作对照药物的米替福新（IC ₅₀为4.05μM）。此外，化合物QDS3表现出选择性作用，其对鞭毛体形式的毒性比对宿主细胞的毒性高40.35倍。另外，用该化合物处理的亚马逊乳杆菌的前鞭毛体在细胞凋亡过程中表现出细胞特征，例如线粒体膜去极化，线粒体肿胀，ROS产生的增加，磷脂酰丝氨酸外化，形状的减小和圆形以及细胞周期的改变。除经治疗的前鞭毛体坏死外，质膜的完整性保持不变。化合物QDS3抑制自噬泡的形成，这可能是通过防止自噬机制去除受损细胞器，加剧由治疗引起的损害，从而导致了寄生虫死亡，从而突出了该化合物的抗衰老作用。此外，配合治疗QDS3感应增加ROS水平在亚马逊利什曼原虫感染的巨噬细胞，但不是在感染宿主细胞。这些数据进一步证明，氧化应激的诱导是通过化合物QDS3的处理在亚马逊乳杆菌中引起的主要毒性作用之一。，造成不可逆转的损害并触发细胞内寄生虫的选择性死亡。此处显示的数据证实了喹啉衍生物的生物活性，并鼓励将来在鼠模型中对该化合物进行体内研究。