2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies

Tarek Mohamed; Praveen P N Rao

doi:10.1016/j.ejmech.2016.12.005

2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies

Eur J Med Chem. 2017 Jan 27:126:823-843. doi: 10.1016/j.ejmech.2016.12.005. Epub 2016 Dec 2.

Authors

Tarek Mohamed¹, Praveen P N Rao²

Affiliations

¹ School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Ave. West., Waterloo, Ontario, N2L 3G1, Canada; Department of Chemistry, University of Waterloo, 200 University Ave. West., Waterloo, Ontario, N2L 3G1, Canada.
² School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Ave. West., Waterloo, Ontario, N2L 3G1, Canada. Electronic address: praopera@uwaterloo.ca.

PMID: 27951490
DOI: 10.1016/j.ejmech.2016.12.005

Abstract

A library of fifty-seven 2,4-disubstituted quinazoline derivatives were designed, synthesized and evaluated as a novel class of multi-targeting agents to treat Alzheimer's disease (AD). The biological assay results demonstrate the ability of several quinazoline derivatives to inhibit both acetyl and butyrylcholinesterase (AChE and BuChE) enzymes (IC₅₀ range = 1.6-30.5 μM), prevent beta-amyloid (Aβ) aggregation (IC₅₀ range 270 nM-16.7 μM) and exhibit antioxidant properties (34-63.4% inhibition at 50 μM). Compound 9 (N²-(1-benzylpiperidin-4-yl)-N⁴-(3,4-dimethoxybenzyl)quinazoline-2,4-diamine) was identified as a dual inhibitor of cholinesterases (AChE IC₅₀ = 2.1 μM; BuChE IC₅₀ = 8.3 μM) and exhibited good inhibition of Aβ aggregation (Aβ40 IC₅₀ = 2.3 μM). Compound 15b (4-(benzylamino)quinazolin-2-ol) was the most potent Aβ aggregation inhibitor (Aβ40 IC₅₀ = 270 nM) and was ∼4 and 1.4-fold more potent compared to the reference agents curcumin and resveratrol. These comprehensive structure activity-relationship (SAR) studies demonstrate the application of a 2,4-disubstituted quinazoline ring as a suitable template to develop multi-targeting agents to treat AD.

Keywords: Alzheimer's disease; Amyloid-beta; Cholinesterase; Molecular modeling; Quinazoline.

MeSH terms

Amyloid beta-Peptides / chemistry*
Antioxidants / chemistry
Antioxidants / metabolism
Antioxidants / pharmacology
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / metabolism
Cholinesterase Inhibitors / pharmacology
Drug Design*
Humans
Molecular Docking Simulation
Peptide Fragments / chemistry*
Protein Aggregates / drug effects*
Protein Conformation
Quinazolines / chemistry*
Quinazolines / metabolism
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antioxidants
Cholinesterase Inhibitors
Peptide Fragments
Protein Aggregates
Quinazolines
amyloid beta-protein (1-40)
amyloid beta-protein (1-42)
Butyrylcholinesterase