Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as dual inhibitors for cholinesterases and amyloid beta aggregation

A new series of tacrine-multialkoxybenzene hybrids (9a–9n) were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced β-amyloid (Aβ) aggregation. All the synthesized compounds had high acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity with IC50 values at the nanomolar range, which were much better than tacrine alone. A Lineweaver–Burk plot and molecular modeling study showed that these hybrids targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, compounds 9a–9f with methylenedioxybenzene moiety showed higher self-induced Aβ aggregation inhibitory activity than a reference compound, curcumin. These compounds could be selected as multi-potent agents for further investigation to treat AD.

Tacrine-multialkoxybenzene hybrids were synthesized as anti-Alzheimer agents with high inhibition activity for both acetylcholinesterase, butyrylcholinesterase and amyloid beta self-aggregation.Figure optionsDownload as PowerPoint slide