Department of Chemistry, Bioscience and Environmental Engineering, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway.
Department of Organic Chemistry, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):2395-2402. doi: 10.1080/14756366.2022.2117912.
The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC = 7-50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.
本文报道了四种杂二聚体的合成，其中采用铜（I）催化的叠氮-炔环加成反应将 1-脱氧野尻霉素部分与苯并三唑支架连接。这些杂二聚体被用作乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制剂进行了研究。在微摩尔浓度范围内（IC = 7-50 μM），杂二聚体对 BuChE 的抑制作用优先（> 9）。对于 BuChE 的最有效抑制剂，使用了 Cornish-Bowden 图，表明它表现为混合抑制剂。对相同抑制剂的建模研究表明，苯并三唑和 1-脱氧野尻霉素部分分别容纳在 AChE 的外周阴离子部位和催化阴离子部位中。与 BuChE 的结合模式不同，因为苯并三唑部分容纳在催化阴离子部位中。
