Structure–Activity Relationship Studies ofIsomeric 24-Diaminoquinazolines on β-Amyloid AggregationKinetics

摘要

A library of isomeric 2,4-diaminoquinazoline (DAQ) derivatives were synthesized and evaluated for antiaggregation potential toward Aβ40/42. Structure–activity relationship data identified compound >3k (N⁴-(4-bromobenzyl)quinazoline-2,4-diamine) with a 4-bromobenzyl substituent as the most potent inhibitor (Aβ40 IC50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (Aβ40 IC50 = 1.5 μM). The corresponding N²-isomer >4k (N²-(4-bromobenzyl)quinazoline-2,4-diamine) was also able to prevent Aβ aggregation (Aβ40 IC50 = 1.7 μM). However, compound >4k exhibited superior inhibition of Aβ42 aggregation (Aβ42 IC50 = 1.7 μM) compared to compound >3k (Aβ42 IC50 = 14.8 μM) and was ∼1.8-fold more potent compared to curcumin (Aβ42 IC50 = 3.1 μM). These results were supported by Aβ 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 Aβ aggregation.