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; Aβ-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; Aβ-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-Aβ-aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.
Keywords: Alzheimer's disease; acetylcholinesterase; beta-amyloid; butyrylcholinesterase; molecular docking; tetrahydroacridin-9-amines.
© 2016 John Wiley & Sons A/S.