PDF(Pubmed)
Abstract：
Triazoles and triazolium salts are very common subunits in the structures of various drugs. Medicaments with a characteristic 1,2,3-triazole core are also being developed to treat neurodegenerative disorders associated with cholinesterase enzyme activity. Several naphtho- and thienobenzo-triazoles from our previous research emerged as being particularly promising in that sense. For this reason, in this research, new naphtho- and thienobenzo-triazoles 23-34, as well as 1,2,3-triazolium salts 44-51, were synthesized and tested. Triazolium salts 44-46 showed excellent activity while salts 47 and 49 showed very good inhibition toward both butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes. In contrast, neutral photoproducts were shown to be selective towards BChE but with very good inhibition potential as molecules 24-27. The representative of newly prepared compounds, 45 and 50, were stable in aqueous solution and revealed intriguing fluorimetric properties, characterized by a strong Stokes shift of >160 nm. Despite their condensed polycyclic structure shaped similarly to well-known DNA-intercalator ethidium bromide, the studied compounds did not show any interaction with ds-DNA, likely due to the unfavorable steric hindrance of substituents. However, the studied dyes bind proteins, particularly showing very diverse inhibition properties toward AChE and BChE. In contrast, neutral photoproducts were shown to be selective towards a certain enzyme but with moderate inhibition potential. The molecular docking of the best-performing candidates to cholinesterases\' active sites identified cation-π interactions as the most responsible for the stability of the enzyme-ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the compounds synthesized have been performed.
摘要：
三唑和三唑盐是各种药物结构中非常常见的亚基。还正在开发具有特征性1,2,3-三唑核心的药物来治疗与胆碱酯酶活性相关的神经退行性疾病。来自我们先前研究的几种萘并和噻吩并-三唑在这个意义上特别有前途。出于这个原因,在这项研究中，合成并测试了新的萘并和噻吩并三唑23-34以及1,2,3-三唑盐44-51。三唑盐44-46显示出优异的活性，而盐47和49对丁酰胆碱酯酶（BChE）和乙酰胆碱酯酶（AChE）均显示出非常好的抑制作用。相比之下,显示中性光产物对BChE具有选择性,但作为分子24-27具有非常好的抑制潜力。新制备的化合物的代表，45和50，在水溶液中稳定，并显示出有趣的荧光特性，特征在于>160nm的强斯托克斯位移。尽管它们的稠合多环结构的形状类似于众所周知的DNA嵌入剂溴化乙锭，研究的化合物没有显示出任何与ds-DNA的相互作用，可能是由于取代基的不利的空间位阻。然而,研究的染料结合蛋白质，特别是对AChE和BChE表现出非常不同的抑制特性。相比之下,中性光产物被证明对某种酶具有选择性，但具有中等的抑制潜力。最佳候选物与胆碱酯酶活性位点的分子对接确定了阳离子-π相互作用是酶-配体复合物稳定性的最大原因。由于遗传毒性研究在开发新的活性物质和成品药物形式时至关重要，已对所有合成的化合物进行了计算机模拟研究。
