Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers

Abstract

The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH₂ groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC₅₀ = 9.7 nM and 11 nM) and BuChE (IC₅₀ = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (ca. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI₅₀ > 100 µM), or to have weak antiproliferative properties (GI₅₀ = 84–97 µM) against a panel of human cancer cells.

Keywords:

• Cholinesterases
• inhibitors
• enantiomers
• modelling
• Alzheimer’s disease

Author contributions

Conceptualisation, E.L.; methodology, I.C.V. and Ó.L.; funding acquisition, E.L, M.O.S., Ó.L., J.M.P., and J.G.F.B.; investigation, E.L, I.C.V, A.P., M.X.F., and Ó.L.; project administration, E.L.; resources, E.L., Ó.L., M.O.S., J.M.P., and J.G.F.B.; supervision, E.L. and M.O.S.; writing – original draft, E.L., I.C.V.; writing – review & editing, E.L., Ó.L., I.C.V., M.O.S., J.M.P., and J.G.F.B.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

The authors (I.C.V., M.O., and E.L.) received financial support from University of Stavanger. This work was supported by Spanish Government for grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033 and Junta de Andalucía (FQM-134) (Ó.L. and J.G.F.-B.). The authors (A.P., M.X.F., and J.M.P.) received financial support from the Spanish Government (Proyecto PID2021-123059OB-I00 financiado por MCIN/AEI/10.13039/501100011033/FEDER, UE). The author (A.P.) received the predoctoral grant from the EU Social Fund (FSE) and the Canary Islands ACIISI for a TESIS2020010055.