title: Structure-Activity Relationship Studies of Isomeric 2,4-Diaminoquinazolines on β-Amyloid Aggregation Kinetics.
abstract: 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 (N (4)-(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 N (2)-isomer 4k (N (2)-(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.
authors.affiliation: School of Pharmacy, Health Sciences Campus, and Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Tarek
authors.initials: T
authors.lastname: Mohamed
authors.affiliation: School of Pharmacy, Health Sciences Campus, and Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Arash
authors.initials: A
authors.lastname: Shakeri
authors.affiliation: School of Pharmacy, Health Sciences Campus, and Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Tin
authors.affiliation: School of Pharmacy, Health Sciences Campus, and Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
keywords: Alzheimer’s disease; Aβ aggregation; Quinazolines; amyloid