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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Yu CW,Chang PT,Hsin LW,Chern JWdoi
10.1021/jm400564jsubject
Has Abstractpub_date
2013-09-12 00:00:00pages
6775-91issue
17eissn
0022-2623issn
1520-4804journal_volume
56pub_type
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