Quinazolin-4-one derivatives as selective histone deacetylase-6 inhibitors for the treatment of Alzheimer's disease
Journal
Journal of Medicinal Chemistry
Journal Volume
56
Journal Issue
17
Pages
6775-6791
Date Issued
2013
Author(s)
Abstract
Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4- dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4b, is the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of α-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated β-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydro- quinazolin-7-yl)-acrylamide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50, 29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 μM) or cytochrome P450 activity (IC50 >6.5 μM) in vitro, and significantly improves learning-based performances of mice with β-amyloid-induced hippocampal lesions. ? 2013 American Chemical Society.
SDGs
Other Subjects
3 (2 cyclopropyl 4 oxo 3 phenethyl 3,4 dihydroquinazolin 7 yl) n hydroxyacrylamide; 3 (2 ethyl 4 oxo 3 phenethyl 3,4 dihydroquinazolin 7 yl) n hydroxyacrylamide; 3 (2 ethyl 6 fluoro 4 oxo 3 phenethyl 3,4 dihydroquinazolin 7 yl)n hydroxyacrylamide; 3 (2 ethyl 7 fluoro 4 oxo 3 phenethyl 3,4 dihydroquinazolin 6 yl) n hydroxyacrylamide; 3 (3 benzyl 2 methyl 4 oxo 3,4 dihydroquinazolin 7 yl) n hydroxyacrylamide; 3 (7 chloro 2 ethyl 4 oxo 3 phenethyl 3,4 dihydroquinazolin 6 yl) n hydroxyacrylamide; 3 [2 ethyl 3 (4 fluorophenethyl) 4 oxo 3,4 dihydroquinazolin 7 yl] n hydroxyacrylamide; 3 [2 ethyl 3 (4 methoxyphenethyl) 4 oxo 3,4 dihydroquinazolin 7 yl] n hydroxyacrylamide; 3 [2 ethyl 4 oxo 3 (3 phenylpropyl) 3,4 dihydroquinazolin 7yl] n hydroxyacrylamide; 4 [(2 ethyl 3,4 dihydro 4 oxo 3 phenethylquinazolin 7 yl)methyl] n hydroxybenzamide; 4 [(2 ethyl 4 oxo 3 phenethyl 3,4 dihydroquinazolin 6 yl)methyl] n hydroxybenzamide; 4 [(2 ethyl 4 oxo 3 phenethyl 3,4 dihydroquinazolin 8 yl)methyl] n hydroxybenzamide; alpha tubulin; amyloid beta protein; cytochrome P450; histone deacetylase 6; histone deacetylase inhibitor; n hydroxy 3 (2 isopropyl 4 oxo 3 phenethyl 3,4 dihydroquinazolin 7 yl)acrylamide; n hydroxy 3 (2 methyl 4 oxo 3 phenethyl 3,4 dihydroquinazolin 7 yl)acrylamide; n hydroxy 3 (2 methyl 4 oxo 3 phenyl 3,4 dihydroquinazolin 5 yl)acrylamide; n hydroxy 3 (2 methyl 4 oxo 3 phenyl 3,4 dihydroquinazolin 6 yl)acrylamide; n hydroxy 3 (2 methyl 4 oxo 3 phenyl 3,4 dihydroquinazolin 7 yl)acrylamide; n hydroxy 3 (2 methyl 4 oxo 3 phenyl 3,4 dihydroquinazolin 8 yl)acrylamide; n hydroxy 3 (4 oxo 3 phenethyl 3,4 dihydroquinazolin 7 yl)acrylamide; n hydroxy 3 [3 [2 (1h indol 3 yl)ethyl] 2 methyl 4 oxo 3,4 dihydroquinazolin 7 yl]acrylamide; neuromodulin; nonhistone protein; potassium channel HERG; quinazoline derivative; unclassified drug; unindexed drug; acetylation; Alzheimer disease; animal experiment; animal model; article; drug design; drug safety; drug synthesis; enzymatic assay; enzyme inhibition; Heck reaction; human; human cell; hydrogen bond; in vitro study; male; microwave irradiation; mouse; nerve fiber growth; nonhuman; protein aggregation; protein expression; Animals; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Magnetic Resonance Spectroscopy; PC12 Cells; Quinazolinones; Rats; Spectrometry, Mass, Electrospray Ionization
Type
journal article