Abstract
Fourteen 5-nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamides (3a-n) were synthesized and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)), as well as their cytotoxicity and MTB isocitrate lyase (ICL) inhibition activity. 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl)-4-[(5-nitro-2,6-dioxohexahydro-4-pyrimidinyl)carbonyl]piperazino-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3n) was found to be the most active compound in vitro with MICs of < 0.17 and 0.17 μM against log-phase MTB and MDR-TB, respectively. Some compounds showed 20-45% inhibition against MTB ICL at 10 μM.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacology*
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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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Chlorocebus aethiops
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Computer Simulation
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Drug Evaluation, Preclinical
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Drug Resistance, Multiple, Bacterial
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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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Inhibitory Concentration 50
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Isocitrate Lyase / antagonists & inhibitors*
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Isocitrate Lyase / chemistry
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Isocitrate Lyase / metabolism
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Ligands
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Microbial Sensitivity Tests
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Molecular Structure
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Mycobacterium / drug effects*
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Mycobacterium / growth & development
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Mycobacterium smegmatis / drug effects
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Mycobacterium smegmatis / growth & development
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Mycobacterium tuberculosis / drug effects
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Mycobacterium tuberculosis / growth & development
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Piperazines
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Protein Binding
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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Quinolines
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Tuberculosis / drug therapy
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Vero Cells
Substances
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1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl)-4-((5-nitro-2,6-dioxohexahydro-4-pyrimidinyl)carbonyl)piperazino-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
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Anti-Bacterial Agents
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Antitubercular Agents
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Bacterial Proteins
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Enzyme Inhibitors
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Ligands
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Piperazines
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Pyrimidines
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Quinolines
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icl protein, Mycobacterium
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Isocitrate Lyase