Chen_2013_Arch.Pharm.(Weinheim)_346_865

Five tacrine-flurbiprofen hybrid compounds (3a-e) were synthesized as multi-target-directed compounds for the treatment of Alzheimer's disease. Compared to tacrine, two compounds (3d and 3e) showed better acetylcholinesterase (AChE) inhibitory activity and others (3b-e) better or the same butyrylcholinesterase (BCHE) inhibitory activity. Notably, 3d showed a mixed-type inhibitory action for AChE, indicating a "dual-binding site action" of both toward the catalytic active site (CAS) and the peripheral anionic site (PAS), whereas for BCHE, a competitive inhibitory action was observed. Furthermore, a cell-based assay on amyloid-beta inhibition demonstrated that the selected target compound 3d effectively inhibits the formation of amyloid-beta in vitro.