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合成及含苯甲酰胺衍生物的生物物理和生物学研究，针对原生动物寄生虫。

Synthesis and Biophysical and Biological Studies of -Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites.

机构信息

Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.

PhD Programme in Medicinal Chemistry, Doctoral School, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.

出版信息

J Med Chem. 2023 Oct 12;66(19):13452-13480. doi: 10.1021/acs.jmedchem.3c00697. Epub 2023 Sep 20.

DOI:10.1021/acs.jmedchem.3c00697
PMID:37729094
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10578353/
Abstract

The AT-rich mitochondrial DNA (kDNA) of trypanosomatid parasites is a target of DNA minor groove binders. We report the synthesis, antiprotozoal screening, and SAR studies of three series of analogues of the known antiprotozoal kDNA binder 2-((4-(4-((4,5-dihydro-1-imidazol-3-ium-2-yl)amino)benzamido)phenyl)amino)-4,5-dihydro-1-imidazol-3-ium (). Bis(2-aminoimidazolines) (1) and bis(2-aminobenzimidazoles) (2) showed micromolar range activity against whereas bisarylimidamides (3) were submicromolar inhibitors of , and . None of the compounds showed relevant activity against the urogenital, nonkinetoplastid parasite . We show that series and bind strongly and selectively to the minor groove of AT DNA, whereas series also binds by intercalation. The measured p indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (Δ) for series and . Compound , which was active and selective against the three parasites and displayed adequate metabolic stability, is a fine candidate for in vivo studies.

摘要

富含 AT 的线粒体 DNA（kDNA）是原生动物寄生虫的靶点，是 DNA 小沟结合物的靶标。我们报告了已知抗原生动物 kDNA 结合物 2-((4-(4-((4,5-二氢-1-咪唑-3-亚基)-2-氨基)苯甲酰胺基)苯基)氨基)-4,5-二氢-1-咪唑-3-亚基 ()的三个系列类似物的合成、抗寄生虫筛选和 SAR 研究。双(2-氨基咪唑啉)（1）和双(2-氨基苯并咪唑)（2）对表现出微摩尔范围内的活性，而双芳基脒（3）则对 、 和 具有亚微摩尔的抑制作用。这些化合物均未显示出对泌尿生殖道、非动基体寄生虫 的相关活性。我们表明，系列 和 可强烈且选择性地与 AT DNA 的小沟结合，而系列 也通过嵌入方式结合。在 pH 7.4 下测量的 p 表明存在不同的离解状态，这与 和 的 DNA 结合亲和力（Δ）相关。化合物 对三种寄生虫均具有活性和选择性，且代谢稳定性良好，是体内研究的良好候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/9458f4ab4b61/jm3c00697_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/4d0acbbd51e9/jm3c00697_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/edc094e0c209/jm3c00697_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/158d1d4066c3/jm3c00697_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/8ef4084d0fea/jm3c00697_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/125d77bcaf54/jm3c00697_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/9458f4ab4b61/jm3c00697_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/4d0acbbd51e9/jm3c00697_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/edc094e0c209/jm3c00697_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/158d1d4066c3/jm3c00697_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/8ef4084d0fea/jm3c00697_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/125d77bcaf54/jm3c00697_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2daa/10578353/9458f4ab4b61/jm3c00697_0003.jpg

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