i3S, Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
IBMC, Instituto de Biologia Molecular e Celular, Porto, Portugal.
Antimicrob Agents Chemother. 2021 Jun 17;65(7):e0151320. doi: 10.1128/AAC.01513-20.
Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, making the need for more effective, safer, and less expensive drugs an urgent one. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in-house antiplasmodial libraries against axenic and intracellular forms of Leishmania infantum, Leishmania amazonensis, and Leishmania major. Several of the screened compounds showed half-maximal inhibitory concentrations (ICs) against intracellular L. infantum parasites in the submicromolar range (compounds 1h, IC = 0.9 μM, and 1n, IC = 0.7 μM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major parasites, albeit in the low micromolar range. Mechanistic studies revealed that compound 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that compound 1n is a promising antileishmanial lead and emphasizes the potential of the quinoline-(1)-imine chemotype for the future development of new antileishmanial agents.
利什曼病是最具挑战性的被忽视热带病之一，仍然对全球公共卫生构成威胁。目前可用的利什曼病疗法存在明显的缺陷，由于寄生虫耐药性，其效率越来越低，因此迫切需要更有效、更安全、更便宜的药物。在我们努力为开发抗利什曼病药物寻找新的化学结构骨架的过程中，我们已经针对无细胞和细胞内形式的婴儿利什曼原虫、亚马逊利什曼原虫和利什曼原虫进行了内部抗疟药物库的筛选。筛选出的几种化合物对亚微摩尔范围内的细胞内 L. infantum 寄生虫具有半数最大抑制浓度 (IC)（化合物 1h，IC = 0.9 μM，和 1n，IC = 0.7 μM），并具有 11 和 9.7 的选择性指数。这些化合物还对亚马逊利什曼原虫和利什曼原虫寄生虫具有活性，尽管活性处于低微摩尔范围内。机制研究表明，化合物 1n 能有效抑制氧消耗并显著降低无细胞利什曼原虫阿米巴虫的线粒体膜电位，表明该类化合物至少部分通过干扰线粒体功能起作用。构效关系分析表明，化合物 1n 是一种很有前途的抗利什曼病先导化合物，并强调了喹啉-(1)-亚胺类化学型在未来开发新型抗利什曼病药物方面的潜力。
