European journal of medicinal chemistry

2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies.

PMID 27951490


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 (IC50 rangexa0=xa01.6-30.5xa0μM), prevent beta-amyloid (Aβ) aggregation (IC50 range 270xa0nM-16.7xa0μM) and exhibit antioxidant properties (34-63.4% inhibition at 50xa0μM). Compound 9 (N(2)-(1-benzylpiperidin-4-yl)-N(4)-(3,4-dimethoxybenzyl)quinazoline-2,4-diamine) was identified as a dual inhibitor of cholinesterases (AChE IC50xa0=xa02.1xa0μM; BuChE IC50xa0=xa08.3xa0μM) and exhibited good inhibition of Aβ aggregation (Aβ40 IC50xa0=xa02.3xa0μM). Compound 15b (4-(benzylamino)quinazolin-2-ol) was the most potent Aβ aggregation inhibitor (Aβ40 IC50xa0=xa0270xa0nM) 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.