Structure-activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease.
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Osman W, Mohamed T, Sit VM, Vasefi MS, Beazely MA, Rao PP
Structure-activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease.
Chem Biol Drug Des. 2016 Nov;88(5):710-723. doi: 10.1111/cbdd.12800. Epub 2016 Jul 11.
- PubMed ID
- 27282589 [ View in PubMed]
- 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 IC(50) = 20 nm; AChE IC(50) = 2.2 mum) and was able to inhibit amyloid aggregation (40% inhibition at 25 mum). Compounds 9e (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC(50) = 0.8 mum; BuChE IC(50) = 1.4 mum; Abeta-aggregation inhibition = 75.7% inhibition at 25 mum) and 11b (6-chloro-N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC(50) = 0.6 mum; BuChE IC(50) = 1.9 mum; Abeta-aggregation inhibition = 85.9% inhibition at 25 mum) 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 (IC(50) = 90 nm). These investigations demonstrate the utility of 3,4-dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti-Abeta-aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.