Abstract
A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 μM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.
Keywords:
InhA; Inhibition; Mycobacterium tuberculosis; Pyrrolidine; Pyrrolidinone; Synthesis.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Antitubercular Agents / chemistry
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Antitubercular Agents / metabolism
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Antitubercular Agents / pharmacology
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism
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Drug Design*
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Escherichia coli / drug effects
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Membrane Transport Proteins / metabolism
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Microbial Sensitivity Tests
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Molecular Docking Simulation
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / metabolism
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Oxidoreductases / antagonists & inhibitors*
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Oxidoreductases / chemistry
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Oxidoreductases / metabolism
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Protein Conformation
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Pyrrolidines / chemistry*
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Pyrrolidines / metabolism
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Pyrrolidines / pharmacology*
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Pyrrolidinones / chemistry*
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Pyrrolidinones / metabolism
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Pyrrolidinones / pharmacology*
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Structure-Activity Relationship
Substances
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Antitubercular Agents
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Bacterial Proteins
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Enzyme Inhibitors
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Membrane Transport Proteins
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MmpL3 protein, Mycobacterium tuberculosis
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Pyrrolidines
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Pyrrolidinones
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Oxidoreductases
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InhA protein, Mycobacterium