Multifunctional tacrine–flavonoid hybrids with cholinergic, β-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer's disease

•A new series of tacrine–flavonoid hybrids (13a–u) were designed and synthesized.•Most of the compounds showed high inhibitory activities for AChE and BuChE.•All compounds could inhibit Aβ aggregation and chelate metal ions.

A new series of tacrine–flavonoid hybrids (13a–u) had been designed, synthesized, and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of the molecules exhibited a significant ability to inhibit ChE and self-induced amyloid-β (Aβ1–42) aggregation. Kinetic and molecular modeling studies also indicated compounds were mixed-type inhibitors, binding simultaneously to active, peripheral and mid-gorge sites of AChE. Particularly, compound 13k was found to be highly potent and showed a balanced inhibitory profile against ChE and self-induced Aβ1–42 aggregation. Moreover, it also showed excellent metal chelating property and low cell toxicity. These results suggested that 13k might be an excellent multifunctional agent for AD treatment.

Graphical abstractA new series of tacrine–flavonoid hybrids were designed and synthesized as multifunctional cholinesterase inhibitors. 13k was found to be a promising compound for further study.Figure optionsDownload full-size imageDownload as PowerPoint slide