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.
