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维生素B6和吡啶-4-甲醛的腙及酰腙衍生物作为抗阿尔茨海默病潜在药物的评估

Evaluation of hydrazone and -acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde as potential drugs against Alzheimer's disease.

作者信息

Bartolić Marija, Matošević Ana, Maraković Nikola, Bušić Valentina, Roca Sunčica, Vikić-Topić Dražen, Sabljić Antonio, Bosak Anita, Gašo-Sokač Dajana

机构信息

Division of Toxicology, Institute for Medical Research and Occupational Health, Zagreb, Croatia.

Faculty of Food and Technology Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.

出版信息

J Enzyme Inhib Med Chem. 2024 Dec;39(1):2431832. doi: 10.1080/14756366.2024.2431832. Epub 2024 Dec 9.

DOI:10.1080/14756366.2024.2431832
PMID:39654394
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11633425/
Abstract

The growing prevalence of Alzheimer's disease calls for a drug that can simultaneously act towards several targets involved in the pathophysiology of the disease. In our study, we evaluated the potential of hydrazone and -acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde to be used as multi-target directed ligands targeting cholinergic system by inhibiting acetyl- and butyrylcholinesterase, lowering the accumulation of β-amyloid plaques by inhibiting both the β-secretase activity and amyloid self-aggregation, and maintaining the biometal balance by chelating certain biometals. Our results showed that all of the tested hydrazones were potent inhibitors of human cholinesterases with inhibition constants (i) in micromolar range able to lower the activity of β-secretase, inhibit amyloid aggregation, chelate biometals and act as antioxidants. Also, most of them were estimated to be able to cross the blood-brain barrier by passive transport and to be absorbed in human intestines as well as with moderate metabolic stability in liver microsomes.

摘要

阿尔茨海默病患病率的不断上升，需要一种能够同时作用于该疾病病理生理学中多个靶点的药物。在我们的研究中，我们评估了维生素B6和吡啶-4-甲醛的腙和酰腙衍生物作为多靶点导向配体的潜力，这些配体通过抑制乙酰胆碱酯酶和丁酰胆碱酯酶来靶向胆碱能系统，通过抑制β-分泌酶活性和淀粉样蛋白自聚集来降低β-淀粉样斑块的积累，并通过螯合某些生物金属来维持生物金属平衡。我们的结果表明，所有测试的腙都是人胆碱酯酶的有效抑制剂，其抑制常数（i）在微摩尔范围内，能够降低β-分泌酶的活性、抑制淀粉样蛋白聚集、螯合生物金属并作为抗氧化剂。此外，据估计，它们中的大多数能够通过被动转运穿过血脑屏障，并在人体肠道中被吸收，在肝微粒体中具有适度的代谢稳定性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/c6879531f64d/IENZ_A_2431832_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/6879a0cca2fe/IENZ_A_2431832_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/0a7603f1bf2d/IENZ_A_2431832_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/7d520e9d4449/IENZ_A_2431832_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/41ff7fb0da7f/IENZ_A_2431832_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/f7601f7ed391/IENZ_A_2431832_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/5f09cd13424d/IENZ_A_2431832_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/c02cd6701b53/IENZ_A_2431832_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/9bcef99adbcb/IENZ_A_2431832_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/1dbf24de9818/IENZ_A_2431832_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/c6879531f64d/IENZ_A_2431832_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/6879a0cca2fe/IENZ_A_2431832_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/0a7603f1bf2d/IENZ_A_2431832_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/7d520e9d4449/IENZ_A_2431832_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/41ff7fb0da7f/IENZ_A_2431832_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/f7601f7ed391/IENZ_A_2431832_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/5f09cd13424d/IENZ_A_2431832_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/c02cd6701b53/IENZ_A_2431832_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/9bcef99adbcb/IENZ_A_2431832_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/1dbf24de9818/IENZ_A_2431832_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5931/11633425/c6879531f64d/IENZ_A_2431832_F0008_C.jpg

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