Preclinical and/or clinical studies have demonstrated the potential of Ivermectin (IVM) for malaria control. In order to improve its antiplasmodial activity and build on previous knowledge, we have designed a third generation of hybrid molecules in which selected pharmacophores were appended to the IVM macrolide, while retaining one or both sugar moieties at the C-13 position. Moreover, we synthesized IVM hybrids that contain structural features of potent IVM metabolites. The evaluation of the in vitro antiplasmodial activity of these compounds against Plasmodium berghei pre-erythrocytic stages and Plasmodium falciparum erythrocytic stages identified molecules that displayed enhanced activity against the latter when compared to IVM. Additionally, two IVM intermediates and one IVM hybrid retained the insecticidal activity of the parental molecule, clarifying the contribution of the sugar moieties to this feature. Altogether, these results provide key structure–activity relationships to guide the rational design of new generations of IVM hybrids.

中文翻译：

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第三代伊维菌素杂交种的抗疟原虫和杀虫活性


临床前和/或临床研究已证明伊维菌素 （IVM） 在疟疾控制方面的潜力。为了提高其抗疟原虫活性并建立在先前知识的基础上，我们设计了第三代杂交分子，其中选定的药效团被附加到 IVM 大环内酯上，同时在 C-13 位置保留一个或两个糖部分。此外，我们合成了包含有效 IVM 代谢物结构特征的 IVM 杂交体。对这些化合物对伯氏疟原虫红细胞前期和恶性疟原虫红细胞阶段的体外抗疟原虫活性的评估确定了与 IVM 相比，对后者表现出增强活性的分子。此外，两种 IVM 中间体和一种 IVM 杂交体保留了亲本分子的杀虫活性，阐明了糖部分对这一特性的贡献。总而言之，这些结果提供了关键的结构-活性关系，以指导新一代 IVM 杂交种的合理设计。