A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). (31st December 2022)

• Record Type: Journal Article
• Authors: Evangelista, Tereza Cristina Santos; López, Óscar; Puerta, Adrián; Fernandes, Miguel X.; Ferreira, Sabrina Baptista; Padrón, José M.; Fernández-Bolaños, José G.; Sydnes, Magne O.; Lindbäck, Emil
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 37:Number 1(2022)
• Page Start: 2395
• Page End: 2402
• Publication Date: 2022-12-31
• Subjects: Iminosugars -- Inhibitors -- Cholinesterases -- Alzheimer's disease; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2117912
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 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 (IC50 = 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.