Development of chalcone-O-alkylamine derivatives as multifunctional agents against Alzheimer's disease

A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50 = 1.3 +/- 0.01 mu M) and butyrylcholinesterase (IC50 = 1.2 +/- 0.09 mu M). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57 +/- 0.01 mu M. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced A beta(1-42) aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu2+-induced A beta(1-42) aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro, and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, A beta(1-42) and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD. (C) 2019 Elsevier Masson SAS. All rights reserved.