Abstract
A series of imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones that potently inhibit M. tuberculosis glutamine synthetase (GlnA1) has been identified by high throughput screening. Exploration of this series was performed owing to a short chemistry program. Despite possibly nanomolar inhibitions, none of these compounds was active on whole cell Mtb, suggesting that GlnA1 may not be a suitable target to find new anti-tubercular drugs.
Keywords:
GlnA1 inhibitors; Glutamine synthetase; High throughput screening; Tuberculosis; X-ray crystallography.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Antitubercular Agents / chemical synthesis
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Antitubercular Agents / chemistry
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Antitubercular Agents / pharmacology*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Glutamate-Ammonia Ligase / antagonists & inhibitors*
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Glutamate-Ammonia Ligase / metabolism
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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High-Throughput Screening Assays
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Models, Molecular
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Molecular Structure
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / enzymology
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Pyrazines / chemical synthesis
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Pyrazines / chemistry
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Pyrazines / pharmacology*
Substances
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Antitubercular Agents
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Enzyme Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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Imidazoles
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Pyrazines
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glutamine synthetase I
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Glutamate-Ammonia Ligase