Alzheimer's disease (AD), the most common form of
senile dementia, is characterized by high
butyrylcholinesterase (BChE) levels in the brain in later AD stages, for which no treatment is available. Pursuing our studies on selective BChE inhibitors, that may contribute to understand the role of this
enzyme in
disease progression, we present now microwave-assisted synthesis and
anticholinesterase activity of a new
nucleoside series embodying
6-chloropurine or 2-acetamido-6-chloropurine linked to D-glucosyl, D-galactosyl and D-mannosyl residues. It was designed to assess the contribution of
sugar stereochemistry,
purine structure and linkage to the
sugar for
cholinesterase inhibition efficiency and selectivity. Compounds were subjected to Ellman's assay and their inhibition constants determined. The α-anomers were the most active compounds, while selectivity for BChE or
acetylcholinesterase (AChE) inhibition could be tuned by the
purine base, by the glycosyl moiety and by N(7)-ligation. Some of the
nucleosides were far more potent than the
drug galantamine, and the most promising competitive and selective BChE inhibitor, the N(7)-linked 2-acetamido-α-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE.