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Chem Biol Drug Des ; 88(5): 710-723, 2016 11.
Article in English | MEDLINE | ID: mdl-27282589

ABSTRACT

A library of substituted tetrahydroacridin-9-amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC50  = 20 nm; AChE IC50  = 2.2 µm) and was able to inhibit amyloid aggregation (40% inhibition at 25 µm). Compounds 9e (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50  = 0.8 µm; BuChE IC50  = 1.4 µm; Aß-aggregation inhibition = 75.7% inhibition at 25 µm) and 11b (6-chloro-N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50  = 0.6 µm; BuChE IC50  = 1.9 µm; Aß-aggregation inhibition = 85.9% inhibition at 25 µm) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine-substituted compound 12c (6-chloro-N-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroacridin-9-amine) was the most potent AChE inhibitor (IC50  = 90 nm). These investigations demonstrate the utility of 3,4-dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti-Aß-aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.


Subject(s)
Amines/chemistry , Cholinesterase Inhibitors/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amines/metabolism , Amines/therapeutic use , Amines/toxicity , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Binding Sites , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/therapeutic use , Cholinesterase Inhibitors/toxicity , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Structure-Activity Relationship
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