title: 2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies.
abstract: A library of fifty-seven 2,4-disubstituted quinazoline derivatives were designed, synthesized and evaluated as a novel class of multi-targeting agents to treat Alzheimer's disease (AD). The biological assay results demonstrate the ability of several quinazoline derivatives to inhibit both acetyl and butyrylcholinesterase (AChE and BuChE) enzymes (IC50range = 1.6-30.5 μM), prevent beta-amyloid (Aβ) aggregation (IC50range 270 nM-16.7 μM) and exhibit antioxidant properties (34-63.4% inhibition at 50 μM). Compound 9 (N2-(1-benzylpiperidin-4-yl)-N4-(3,4-dimethoxybenzyl)quinazoline-2,4-diamine) was identified as a dual inhibitor of cholinesterases (AChE IC50= 2.1 μM; BuChE IC50= 8.3 μM) and exhibited good inhibition of Aβ aggregation (Aβ40 IC50= 2.3 μM). Compound 15b (4-(benzylamino)quinazolin-2-ol) was the most potent Aβ aggregation inhibitor (Aβ40 IC50= 270 nM) and was ∼4 and 1.4-fold more potent compared to the reference agents curcumin and resveratrol. These comprehensive structure activity-relationship (SAR) studies demonstrate the application of a 2,4-disubstituted quinazoline ring as a suitable template to develop multi-targeting agents to treat AD.
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Ave. West., Waterloo, Ontario, N2L 3G1, Canada; Department of Chemistry, University of Waterloo, 200 University Ave. West., Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Tarek
authors.initials: T
authors.lastname: Mohamed
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Ave. West., Waterloo, Ontario, N2L 3G1, Canada. Electronic address: praopera@uwaterloo.ca.
authors.forename: Praveen P N
authors.initials: PPN
authors.lastname: Rao
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D066329:Protein Aggregates / Q000187:drug effects*; D011487:Protein Conformation; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; D066329:Protein Aggregates; D011799:Quinazolines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Amyloid-beta; Cholinesterase; Molecular modeling; Quinazoline