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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
19
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pubmed:dateCreated |
2007-9-13
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pubmed:abstractText |
FabI and FabK are bacterial enoyl-acyl carrier protein (ACP) reductases that catalyze the final and rate-limiting step of bacterial fatty acid biosynthesis (FAS) and are potential targets of novel antibacterial agents. We have reported 4-pyridone derivative 3 as a FabI inhibitor and phenylimidazole derivative 5 as a FabK inhibitor. Here, we will report phenylimidazole derivatives of 4-pyridone as FabI and FabK dual inhibitors based on an iterative medicinal chemistry and crystallographic study of FabK from Streptococcus pneumoniae/compound 26. A representative compound 6 showed strong FabI inhibitory (IC50 = 0.38 microM) and FabK inhibitory (IC50 = 0.0045 microM) activities with potent antibacterial activity against S. pneumoniae (MIC = 0.5 microg/mL). Since elevated MIC value was observed against S. pneumoniae mutant possessing one amino acid substitution in FabK, the antibacterial activity of the compound was considered to be due to the inhibition of FabK. Moreover, this compound showed no significant cytotoxicity (IC50 > 69 microM). These results support compound 6 as a novel agent for the treatment of bacterial infections.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Bacterial Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Bacterial Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Benzothiazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Enoyl-(Acyl-Carrier-Protein)...,
http://linkedlifedata.com/resource/pubmed/chemical/Escherichia coli Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Fatty Acid Synthetase Complex...,
http://linkedlifedata.com/resource/pubmed/chemical/Fatty Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridones,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Urea,
http://linkedlifedata.com/resource/pubmed/chemical/fabI protein, E coli
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
20
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4710-20
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:17713898-Anti-Bacterial Agents,
pubmed-meshheading:17713898-Bacterial Proteins,
pubmed-meshheading:17713898-Benzothiazoles,
pubmed-meshheading:17713898-Binding Sites,
pubmed-meshheading:17713898-Cell Line, Tumor,
pubmed-meshheading:17713898-Crystallography, X-Ray,
pubmed-meshheading:17713898-Enoyl-(Acyl-Carrier-Protein) Reductase (NADH),
pubmed-meshheading:17713898-Escherichia coli Proteins,
pubmed-meshheading:17713898-Fatty Acid Synthetase Complex, Type II,
pubmed-meshheading:17713898-Fatty Acids,
pubmed-meshheading:17713898-Humans,
pubmed-meshheading:17713898-Imidazoles,
pubmed-meshheading:17713898-Microbial Sensitivity Tests,
pubmed-meshheading:17713898-Models, Molecular,
pubmed-meshheading:17713898-Molecular Structure,
pubmed-meshheading:17713898-Mutation,
pubmed-meshheading:17713898-Pyridones,
pubmed-meshheading:17713898-Staphylococcus aureus,
pubmed-meshheading:17713898-Streptococcus pneumoniae,
pubmed-meshheading:17713898-Thiazoles,
pubmed-meshheading:17713898-Urea
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pubmed:year |
2007
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pubmed:articleTitle |
Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl-acyl carrier protein reductases FabI and FabK.
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pubmed:affiliation |
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. hideo_kitagawa@meiji.co.jp
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pubmed:publicationType |
Journal Article
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