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

ABSTRACT: A library of isomeric 2,4-diaminoquinazoline (DAQ) derivatives were synthesized and evaluated for antiaggregation potential toward A?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?40 IC50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (A?40 IC50 = 1.5 ?M). The corresponding N (2)-isomer 4k (N (2)-(4-bromobenzyl)quinazoline-2,4-diamine) was also able to prevent A? aggregation (A?40 IC50 = 1.7 ?M). However, compound 4k exhibited superior inhibition of A?42 aggregation (A?42 IC50 = 1.7 ?M) compared to compound 3k (A?42 IC50 = 14.8 ?M) and was ?1.8-fold more potent compared to curcumin (A?42 IC50 = 3.1 ?M). These results were supported by A? 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? aggregation.

SUBMITTER: Mohamed T 

PROVIDER: S-EPMC4867481 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature