Structure-activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease.
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 nm; AChE IC50= 2.2 μm) and was able to inhibit amyloid aggregation (40% inhibition at 25 μm). Compounds 9e (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50= 0.8 μm; BuChE IC50= 1.4 μm; Aβ-aggregation inhibition = 75.7% inhibition at 25 μm) and 11b (6-chloro-N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50= 0.6 μm; BuChE IC50= 1.9 μm; Aβ-aggregation inhibition = 85.9% inhibition at 25 μm) 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 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.
School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada.
Wesseem
W
Osman
School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada.|Department of Chemistry, University of Waterloo, Waterloo, ON, Canada.
Tarek
T
Mohamed
School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada.
Victor Munsing
VM
Sit
School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada.
Maryam S
MS
Vasefi
School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada.
Michael A
MA
Beazely
School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, ON, Canada. praopera@uwaterloo.ca.
Praveen P N
PP
Rao
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D000588:Amines; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Alzheimer's disease; acetylcholinesterase; beta-amyloid; butyrylcholinesterase; molecular docking; tetrahydroacridin-9-amines