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第三代伊维菌素杂合化合物的抗疟原虫和杀虫活性。

Antiplasmodial and Insecticidal Activities of Third-Generation Ivermectin Hybrids.

机构信息

Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India.

Gulbenkian Institute for Molecular Medicine, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.

出版信息

J Med Chem. 2024 Nov 28;67(22):20224-20241. doi: 10.1021/acs.jmedchem.4c01606. Epub 2024 Nov 6.

DOI:10.1021/acs.jmedchem.4c01606
PMID:39505355
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11613448/
Abstract

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 antiplasmodial activity of these compounds against pre-erythrocytic stages and 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.

摘要

临床前和/或临床研究已经证明伊维菌素（IVM）在疟疾控制方面具有潜力。为了提高其抗疟原虫活性并利用以前的知识，我们设计了第三代杂合分子，其中选择的药效团连接到 IVM 大环内酯上，同时保留 C-13 位置上的一个或两个糖基。此外，我们合成了含有有效 IVM 代谢物结构特征的 IVM 杂合物。这些化合物对原虫阶段和红细胞阶段的抗疟原虫活性评估确定了与 IVM 相比对后者具有增强活性的分子。此外，两种 IVM 中间体和一种 IVM 杂合物保留了母体分子的杀虫活性，这阐明了糖基对此特性的贡献。总之，这些结果提供了关键的结构-活性关系，以指导新代 IVM 杂合物的合理设计。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/619283ac3e1e/jm4c01606_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/37fd30fae35a/jm4c01606_0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/f37c60730061/jm4c01606_0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/619283ac3e1e/jm4c01606_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/37fd30fae35a/jm4c01606_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/c46705533107/jm4c01606_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/00c517c36c60/jm4c01606_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/453b8c1d3f24/jm4c01606_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/b93f0ddea24d/jm4c01606_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/f37c60730061/jm4c01606_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/7e5632fca6d8/jm4c01606_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/62f2a9573b86/jm4c01606_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84a9/11613448/619283ac3e1e/jm4c01606_0005.jpg

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本文引用的文献

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Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes.伊维菌素代谢物的药代动力学及其对致倦库蚊的活性。
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Activity of Ivermectin and Its Metabolites against Asexual Blood Stage Plasmodium falciparum and Its Interactions with Antimalarial Drugs.
伊维菌素及其代谢物对无性血期疟原虫的活性及其与抗疟药物的相互作用。
Antimicrob Agents Chemother. 2023 Jul 18;67(7):e0173022. doi: 10.1128/aac.01730-22. Epub 2023 Jun 20.
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Ivermectin metabolites reduce Anopheles survival.伊维菌素代谢物降低按蚊存活率。
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