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Structure–activity relationship studies of benzyl‐, phenethyl‐, and pyridyl‐substituted tetrahydroacridin‐9‐amines as multitargeting agents to treat Alzheimer's disease
Author(s) -
Osman Wesseem,
Mohamed Tarek,
Sit Victor Munsing,
Vasefi Maryam S.,
Beazely Michael A.,
Rao Praveen P. N.
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12800
Subject(s) - butyrylcholinesterase , chemistry , ic50 , amine gas treating , cholinesterase , acetylcholinesterase , pharmacophore , aché , stereochemistry , enzyme , biochemistry , pharmacology , in vitro , organic chemistry , medicine
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 n m ; AC hE IC 50 = 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, AC hE IC 50 = 0.8 μ m ; BuChE IC 50 = 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, AC hE IC 50 = 0.6 μ m ; BuChE IC 50 = 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 AC hE inhibitor ( IC 50 = 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.