Structure–activity relationship studies of benzyl‐, phenethyl‐, and pyridyl‐substituted tetrahydroacridin‐9‐amines as multitargeting agents to treat Alzheimer's disease. (11th July 2016)

• Record Type: Journal Article
• Authors: Osman, Wesseem; Mohamed, Tarek; Sit, Victor Munsing; Vasefi, Maryam S.; Beazely, Michael A.; Rao, Praveen P. N.
• Is Part Of: Chemical biology & drug design. Volume 88:Number 5(2016)
• Page Start: 710
• Page End: 723
• Publication Date: 2016-07-11
• Subjects: acetylcholinesterase -- Alzheimer's disease -- beta‐amyloid -- butyrylcholinesterase -- molecular docking -- tetrahydroacridin‐9‐amines; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12800
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : A library of substituted tetrahydroacridin‐9‐amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound8e ( 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 μ m ) and was able to inhibit amyloid aggregation (40% inhibition at 25 μ m ). Compounds9e (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 ) and11b (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 compound12c (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. Abstract : Anti‐Alzheimer's agents with potent cholinesterase and beta‐amyloid aggregation inhibition were identified. Tetrahydroacridin‐9‐amine derivatives with nanomolar‐scale inhibition of both acetyl‐ and butyrylcholinesterase were discovered. A 3, 4‐dimethoxyphenyl substituent was identified as an antiamyloid pharmacophore.