Revisiting Purine Nucleoside Cholinesterase Inhibitors - An Experimental Glycon Structure/Activity Relationship Study

Abstract

Background: A new family of purine nucleoside cholinesterase inhibitors was disclosed by us, with potency and selectivity over acetylcholinesterase or butyrylcholinesterase controlled by tuning structural and stereochemical features of nucleosides with perbenzylated glycosyl moieties.

Objective: Design, synthesis, and biological evaluation of new purine nucleosides were used to investigate glycon protecting group pattern required for anticholinesterase activity and selectivity.

Methods: Regioselective chemistry to introduce methyl/benzyl groups in glycon donors and Nglycosylation was used to acquire the target nucleosides. Evaluation of their biological potential and selectivity as cholinesterase inhibitors was performed.

Results: Synthetic strategies chosen resulted in high glycon donor's overall yield and regio- and stereoselectivity was found in N-glycosylation reaction. Some of the new nucleosides are cholinesterase inhibitors and selectivity for butyrylcholinesterase was also achieved.

Conclusion: N-glycosylation reaction was stereoselective for the β-anomers while regioselectivity was achieved for the N⁹ isomers when glycon positions 2 and 3 were methylated. Cholinesterase inhibition was found when the 2,3-di-O-benzyl-4-O-methyl pattern is present in the sugar moiety. Amongst the new compounds, the two most promising ones showed micromolar inhibition (mixed inhibition), being one of them selective for butyrylcholinesterase inhibition.

Keywords: ACht; AD; Purine nucleosides; anticholinesterase activity; selectivity; stereoselective synthesis.