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

作者：Mohamed Tarek; Rao Praveen P N^*

来源：European Journal of Medicinal Chemistry, 2017, 126: 823-843.

DOI：10.1016/j.ejmech.2016.12.005

• Alzheimer's disease
• Amyloid-beta
• Cholinesterase
• Quinazoline
• Molecular modeling

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 mu M), prevent beta-amyloid (A beta) aggregation (IC50 range 270 nM-16.7 mu M) and exhibit antioxidant properties (34-63.4% inhibition at 50 mu M). 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 IC50 = 2.1 mu M); BuChE IC50 = 8.3 mu M) and exhibited good inhibition of A beta aggregation (A beta 40 IC50 = 2.3 mu M). Compound 15b (4-(benzylamino) quinazolin-2-ol) was the most potent A beta aggregation inhibitor (A beta 40 IC50 = 270 nM) and was similar to 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.

• 出版日期2017-1-27