Abstract
This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1 H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Animals
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Binding Sites
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Blood-Brain Barrier / drug effects
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Cell Line
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Disease Models, Animal
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Female
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Histone Deacetylase 6 / antagonists & inhibitors*
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Histone Deacetylase 6 / chemistry
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Histone Deacetylase 6 / metabolism
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Histone Deacetylase Inhibitors / chemical synthesis
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Histone Deacetylase Inhibitors / chemistry*
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Histone Deacetylase Inhibitors / pharmacology*
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Humans
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Hydroxamic Acids / chemistry
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Indoles / chemistry*
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Indoles / pharmacology
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Male
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Memory and Learning Tests
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Mice, Transgenic
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Molecular Docking Simulation
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Phosphorylation / drug effects
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Rats, Sprague-Dawley
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Rats, Wistar
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Ubiquitination / drug effects
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tau Proteins / metabolism
Substances
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Indoles
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Neuroprotective Agents
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tau Proteins
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HDAC6 protein, human
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Histone Deacetylase 6