title: Design, synthesis and structure-activity relationship (SAR) studies of 2,4-disubstituted pyrimidine derivatives: dual activity as cholinesterase and Aβ-aggregation inhibitors.
abstract: A novel class of 2,4-disubstituted pyrimidines (7a-u, 8a-f, 9a-e) that possess substituents with varying steric and electronic properties at the C-2 and C-4 positions, were designed, synthesized and evaluated as dual cholinesterase and amyloid-β (Aβ)-aggregation inhibitors. In vitro screening identified N-(naphth-1-ylmethyl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (9a) as the most potent AChE inhibitor (IC(50)=5.5 μM). Among this class of compounds, 2-(4-methylpiperidin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine (9e) was identified as the most potent and selective BuChE inhibitor (IC(50)=2.2 μM, selectivity index=11.7) and was about 5.7-fold more potent compared to the commercial, approved reference drug galanthamine (BuChE IC(50)=12.6 μM). In addition, the selective AChE inhibitor N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine (7d), exhibited good inhibition of hAChE-induced aggregation of Aβ(1-40) fibrils (59% inhibition). Furthermore, molecular modeling studies indicate that a central pyrimidine ring serves as a suitable template to develop dual inhibitors of cholinesterase and AChE-induced Aβ aggregation thereby targeting multiple pathological routes in AD.
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Tarek
authors.initials: T
authors.lastname: Mohamed
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.forename: Lila K
authors.initials: LK
authors.lastname: Habib
authors.forename: Jerry
authors.initials: J
authors.lastname: Yang
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D011743:Pyrimidines