Design, Synthesis and Evaluation of Novel Dimethylamino Chalcone-O-alkylamines Derivatives As Potential Multifunctional Agents Against Alzheimer's Disease.

A novel series of dimethylamino chalcone-O-alkylamines derivatives was designed and synthesized as multifunctional agents for the treatment of AD. All the target compounds exhibited significant abilities to inhibit and disaggregate A beta aggregation, and acted as potential selective AChE inhibitors, biometal chelators and selective MAO-B inhibitors. Among these compounds, compound TM-6 showed the greatest inhibitory activity against self-induced A beta aggregation (IC50 = 0.88 mu M) and well disaggregation ability toward self-induced Ab aggregation (95.1%, 25 mu M), the TEM images, molecular docking study and molecular dynamics simulations provided reasonable explanation for its high efficiency, and it was also found to be a remarkable antioxidant (ORAC-FL values of 2.1eq.), the best AChE inhibitor (IC50 = 0.13 mM) and MAO-B inhibitor (IC50 = 1.0 mM), as well as a good neuroprotectant. UVevisual spectrometry and ThT fluorescence assay revealed that compound TM-6 was not only a good biometal chelator by inhibiting Cu2+-induced A beta aggregation (95.3%, 25 mu M) but also could disassemble the well-structured Ab fibrils (88.1%, 25 mM). Further, TM-6 could cross the blood-brain barrier (BBB) in vitro. More importantly, compound TM-6 did not show any acute toxicity in mice at doses of up to 1000 mg/kg and improved scopolamine-induced memory impairment. Taken together, these data indicated that TM-6, an excellent balanced multifunctional inhibitor, was a potential lead compound for the treatment of AD. (C) 2021 Elsevier Masson SAS. All rights reserved.