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

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 CH(2) 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 (IC(50) = 9.7 nM and 11 nM) and BuChE (IC(50) = 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 (GI(50) > 100 µM), or to have weak antiproliferative properties (GI(50) = 84–97 µM) against a panel of human cancer cells.