Endochin-like quinolones (ELQs) define a class of small molecule antimicrobials that target the mitochondrial electron transport chain of various human parasites by inhibiting their cytochrome bc₁ complexes. The compounds have shown potent activity against a wide range of protozoan parasites, including the intraerythrocytic parasites Plasmodium and Babesia, the agents of human malaria and babesiosis, respectively. First-generation ELQ compounds were previously found to reduce infection by Babesia microti and Babesia duncani in animal models of human babesiosis but achieved a radical cure only in combination with atovaquone and required further optimization to address pharmacological limitations. Here, we report the identification of two second-generation 3-biaryl ELQ compounds, ELQ-596 and ELQ-650, with potent antibabesial activity in vitro and favorable pharmacological properties. In particular, ELQ-598, a prodrug of ELQ-596, demonstrated high efficacy as an orally administered monotherapy at 10 mg/kg. The compound achieved radical cure in both the chronic model of B. microti-induced babesiosis in immunocompromised mice and the lethal infection model induced by B. duncani in immunocompetent mice. Given its high potency, favorable physicochemical properties, and low toxicity profile, ELQ-596 represents a promising drug for the treatment of human babesiosis.

中文翻译：

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两种新型内啡肽样喹诺酮类药物 ELQ-596 和 ELQ-650 在人类巴贝虫病实验小鼠模型中的有效性

类内啡肽喹诺酮类 (ELQ) 定义了一类小分子抗菌剂，通过抑制各种人类寄生虫的细胞色素 bc ₁复合物来靶向其线粒体电子传递链。这些化合物对多种原生动物寄生虫显示出有效的活性，包括红细胞内寄生虫疟原虫和巴贝虫病，它们分别是人类疟疾和巴贝斯虫病的病原体。此前发现第一代 ELQ 化合物可以减少人类巴贝虫病动物模型中田鼠巴贝虫和邓氏巴贝虫的感染，但只有与阿托伐醌联合使用才能实现根治，并且需要进一步优化以解决药理学限制。在此，我们报告了两种第二代 3-联芳基 ELQ 化合物 ELQ-596 和 ELQ-650 的鉴定，它们具有有效的体外抗巴贝斯活性和良好的药理学特性。特别是，ELQ-598（ELQ-596 的前药）作为口服单一疗法（10 mg/kg）表现出高效能。该化合物在免疫功能低下小鼠中的田鼠巴贝西虫病慢性模型和免疫功能正常小鼠中由邓肯巴贝西虫引起的致死性感染模型中均实现了根治性治愈。鉴于其高效力、良好的理化特性和低毒性，ELQ-596 是一种有前途的治疗人类巴贝虫病的药物。