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- Title
Structure-activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease.
- Authors
Osman, Wesseem; Mohamed, Tarek; Sit, Victor Munsing; Vasefi, Maryam S.; Beazely, Michael A.; Rao, Praveen P. N.
- 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 n m; AChE IC50 = 2.2 μ m) and was able to inhibit amyloid aggregation (40% inhibition at 25 μ m). Compounds 9e (6-chloro- N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50 = 0.8 μ m; BuChE IC50 = 1.4 μ m; Aβ-aggregation inhibition = 75.7% inhibition at 25 μ m) and 11b (6-chloro- N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50 = 0.6 μ m; BuChE IC50 = 1.9 μ m; Aβ-aggregation inhibition = 85.9% inhibition at 25 μ m) 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 n m). 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.
- Subjects
STRUCTURE-activity relationships; ALZHEIMER'S disease; CHOLINESTERASES; AMYLOID; BUTYRYLCHOLINESTERASE
- Publication
Chemical Biology & Drug Design, 2016, Vol 88, Issue 5, p710
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12800