Hybrids of oxoisoaporphine-tacrine congeners: Novel acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation inhibitors

A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tacrine or its congener, connected through an oligomethylene linker containing an amine group at variable position. These hybrids exhibit high AChE inhibitory activity with IC50 values in the nanomolar range in most cases. Moreover, five out of the 12 hybrids of this series, particularly those bearing a tetrahydroacridine moiety, exhibit a significant in vitro inhibitory activity toward the AChE-induced and self-induced Aβ aggregation, which makes them promising anti-Alzheimer drug candidates.

Graphical AbstractA series of dual binding site (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced β-amyloid aggregation.Figure optionsDownload as PowerPoint slideHighlights
► Oxoisoaporphine derivatives acetylcholinesterase and butyrylcholinesterase inhibitor.
► Five hybrids acetylcholinesterase inhibitor with IC50 values in the nanomolar range.
► All the tested hybrids exhibited significant Aβ-antiaggregating effect.