Structure-activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease.

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 =20nm; AChE IC50 =2.2μm) and was able to inhibit amyloid aggregation (40% inhibition at 25μm). Compounds 9e (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50 =0.8μm; BuChE IC50 =1.4μm; Aβ-aggregation inhibition=75.7% inhibition at 25μm) and 11b (6-chloro-N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50 =0.6μm; BuChE IC50 =1.9μm; Aβ-aggregation inhibition=85.9% inhibition at 25μm) 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 =90nm). 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.