Abstract
We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-D-ribose2'-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Oxidoreductases
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Animals
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Antitubercular Agents / pharmacokinetics
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Antitubercular Agents / pharmacology*
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Antitubercular Agents / therapeutic use
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Bacterial Proteins / antagonists & inhibitors*
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Drug Discovery
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Indoles / therapeutic use
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Mice
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Mycobacterium tuberculosis / drug effects*
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Oxidoreductases / antagonists & inhibitors*
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Rats
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Tuberculosis, Multidrug-Resistant / drug therapy
Substances
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Antitubercular Agents
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Bacterial Proteins
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Enzyme Inhibitors
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Indoles
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Oxidoreductases
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Alcohol Oxidoreductases
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DprE1 protein, Mycobacterium tuberculosis