Structure-Activity Relationship Studies of Isomeric 2,4-Diaminoquinazolines on beta-Amyloid Aggregation Kinetics

摘要

A library of isomeric 2,4-diaminoquinazoline (DAQ) derivatives were synthesized and evaluated for antiaggregation potential toward A beta 40/42. Structure activity relationship data identified compound 3k (N-4-(4-bromobenzyl)-quinazoline-2,4-diamine) with a 4-bromobenzyl substituent as the most potent inhibitor (A beta 40 IC50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (A beta 40 IC50 = 1.5 mu M). The corresponding N-2-isomer 4k (N-2-(4-bromobenzyl)quinazoline-2,4-diamine) was also able to prevent A beta aggregation (A beta 40 IC50 = 1.7 mu M). However, compound 4k exhibited superior inhibition of A beta 42 aggregation (A beta 42 IC50 = 1.7 mu M) compared to compound 3k (A beta 42 IC50 = 14.8 mu M) and was similar to 1.8-fold more potent compared to curcumin (A beta 42 IC50 = 3.1 mu M). These results were supported by A beta aggregation kinetics investigations and transmission electron microscopy studies, which demonstrate the suitability of DAQ ring system to develop antiamyloid agents as pharmacological tools to study A beta aggregation.