高效获取新型噻吩并-1,2,3-三唑鎓盐作为首选的双重胆碱酯酶抑制剂。

IF 4.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Biomolecules Pub Date : 2024-10-31 DOI:10.3390/biom14111391
Milena Mlakić, Maja Sviben, Ana Ratković, Anamarija Raspudić, Danijela Barić, Ivana Šagud, Zlata Lasić, Ilijana Odak, Irena Škorić
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引用次数: 0

摘要

在以前的研究中,1,2,3-三唑盐作为胆碱酯酶(ChEs)的潜在抑制剂显示出了显著的生物活性,而胆碱酯酶对神经传递至关重要。本研究制备了一对不带电的噻吩并三唑及其带电盐,以进一步研究三唑环氮上的正电荷在酶活性位点内相互作用的作用,并比较 1,2,3-三唑盐与通过光化学环化获得的不带电类似物的选择性。中性噻吩并三唑对丁酰胆碱酯酶(BChE)表现出很好的选择性活性,而它们的盐类对 BChE(最活跃的 23:IC50 0.47 μM)和乙酰胆碱酯酶(AChE)(最活跃的 23:IC50 4.4 μM)都表现出很好的非选择性抑制作用。这些含有 1,2,3-三唑盐的新结构为药物开发提供了新的支架,因为众所周知,目前治疗阿尔茨海默病(AD)的药物包括选择性 AChE 抑制剂,而对于帕金森病和所有阶段的 AD,非选择性胆碱酯酶抑制剂是首选。我们对所选化合物及其相应盐类与胆碱酯酶活性位点进行了分子对接,以确定导致非共价胆碱酯酶配体稳定性的相互作用。由于遗传毒性研究对于开发新的活性物质和药物成品至关重要,因此对所有合成化合物进行的硅学研究表明,化合物 18 是最有希望获得遗传毒性安全性的候选化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Efficient Access to New Thienobenzo-1,2,3-Triazolium Salts as Preferred Dual Cholinesterase Inhibitors.

In previous research, 1,2,3-triazolium salts showed significant biological activity as potential inhibitors of cholinesterase enzymes (ChEs), which are crucial for neurotransmission. In this research, pairs of uncharged thienobenzo-triazoles and their charged salts were prepared in order to further examine the role of the positive charge on the nitrogen of the triazole ring in interactions within the active site of the enzymes, and to compare the selectivity of 1,2,3-triazolium salts in relation to their uncharged analogs obtained by photochemical cyclization. Neutral thienobenzo-triazoles showed very good selective activity toward butyrylcholinesterase (BChE), while their salts showed excellent non-selective inhibition toward both BChE (the most active 23: IC50 0.47 μM) and acetylcholinesterase (AChE) enzymes (the most active 23: IC50 4.4 μM). These new structures with incorporated 1,2,3-triazolium salts present the new scaffold for drug development as it is known that the current therapy in Alzheimer's disease (AD) comprises selective AChE inhibitors, while in Parkinson's and all stages of AD, non-selective inhibitors of ChEs are preferred. Molecular docking of the selected compounds and their corresponding salts into the active sites of ChEs was conducted to identify the interactions responsible for the stability of the non-covalent cholinesterase-ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the synthesized compounds have shown that compound 18 is the most promising candidate for genotoxic safety.

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来源期刊
Biomolecules
Biomolecules Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
3.60%
发文量
1640
审稿时长
18.28 days
期刊介绍: Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications.  Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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