“Clicking“ fragment leads to novel dual-binding cholinesterase inhibitors

Zuzanna Molęda, Anna Zawadzka, Zbigniew Czarnocki, Leticia Monjas, Anna K.H. Hirsch, Armand Budzianowski, Jan K. Maurin


Graphical abstract


Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer’s disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using “clickable” fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC50 = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.

Keywords: Galantamine; Tryptamine; Tetrahydroisoquinoline; Triazole; ”click” chemistry; Target-guided synthesis; Hybrid drugs; Structure-activity relationship; Combinatorial libraries