1. Design, synthesis and evaluation of novel dimethylamino chalcone-O-alkylamines derivatives as potential multifunctional agents against Alzheimer's disease.
- Author
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Sang Z, Song Q, Cao Z, Deng Y, Tan Z, and Zhang L
- Subjects
- Acetylcholinesterase chemistry, Acetylcholinesterase metabolism, Alzheimer Disease drug therapy, Alzheimer Disease pathology, Amines metabolism, Amines pharmacology, Amines therapeutic use, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides metabolism, Animals, Antioxidants chemistry, Binding Sites, Cell Survival drug effects, Chalcone chemistry, Humans, Kinetics, Metals chemistry, Metals metabolism, Molecular Docking Simulation, Monoamine Oxidase chemistry, Monoamine Oxidase metabolism, Neuroprotective Agents metabolism, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, PC12 Cells, Protein Aggregates drug effects, Rats, Structure-Activity Relationship, Amines chemistry, Drug Design, Neuroprotective Agents chemistry
- Abstract
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 Aβ 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 Aβ aggregation (IC50 = 0.88 μM) and well disaggregation ability toward self-induced Aβ aggregation (95.1%, 25 μM), 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 μM) and MAO-B inhibitor (IC50 = 1.0 μM), as well as a good neuroprotectant. UV-visual spectrometry and ThT fluorescence assay revealed that compound TM-6 was not only a good biometal chelator by inhibiting Cu2+-induced Aβ aggregation (95.3%, 25 μM) but also could disassemble the well-structured Aβ fibrils (88.1%, 25 μM). 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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