Mohamed_2016_Eur.J.Med.Chem_126_823

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 range = 1.6-30.5 muM), prevent beta-amyloid (Abeta) aggregation (IC50 range 270 nM-16.7 muM) and exhibit antioxidant properties (34-63.4% inhibition at 50 muM). 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 muM; BuChE IC50 = 8.3 muM) and exhibited good inhibition of Abeta aggregation (Abeta40 IC50 = 2.3 muM). Compound 15b (4-(benzylamino)quinazolin-2-ol) was the most potent Abeta aggregation inhibitor (Abeta40 IC50 = 270 nM) and was approximately 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.