A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE)

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2395-2402. doi: 10.1080/14756366.2022.2117912.

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.

Keywords: Alzheimer’s disease; Cholinesterases; Iminosugars; Inhibitors.

MeSH terms

  • 1-Deoxynojirimycin
  • Acetylcholinesterase* / metabolism
  • Butyrylcholinesterase* / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Triazoles

Substances

  • Cholinesterase Inhibitors
  • Triazoles
  • 1-Deoxynojirimycin
  • benzotriazole
  • Acetylcholinesterase
  • Butyrylcholinesterase

Grants and funding

Ó.L. and J.G.F.-B. thank the Spanish Government for grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033, and Junta de Andalucía (FQM-134). A.P. thanks the EU Social Fund (FSE) and the Canary Islands ACIISI for a predoctoral grant TESIS2020010055. A.P., M.X.F., and J.M.P. thank the Canary Islands Government (ACIISI/FEDER, UE, grant number ProID2020010101) for financial support. T.C.SE would like to thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) for a PhD fellowship (Finance Code 001) and the PRINT-CAPES program for the sandwich doctoral scholarship.