脂肪酸生合成におけるエノイルACP還元酵素 FabI と FabK 阻害による抗菌薬の探索 Search for the Dual Inhibitors of Bacterial Enoyl-acyl Carrier Protein (ACP) Reductases (FabI and FabK) as Antibacterial Agents

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Bacterial enoyl-acyl carrier protein (ACP) reductases (FabI and FabK) catalyze the final step in each cycle of fatty acid biosynthesis and are attractive targets for the development of new antibacterial agents. Here, we report the development of novel phenylimidazole derivatives as potent FabK inhibitors with antibacterial activity against Streptococcus pneumoniae. A representative compound, 1-{[4-(4-bromophenyl)-1H-imidazol-2-yl]methyl}-3-[5-(pyridin-2-ylthio)thiazol-2-yl]urea (53) showed strong FabK-inhibitory activity (S. pneumoniae FabK IC50 0.0024µM) and potent in vitro antibacterial activity against S. pneumoniae (MIC 0.25 µg/mL). MIC50 and MIC90 of compound 53 against 29 clinical isolates of S. pneumoniae, including penicillin-resistant strains, were 1 and 4µg/mL, respectively. Since an elevated MIC value was observed with a S. pneumoniae mutant possessing an 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. These results suggest that compound 53 is a candidate for anti-pneumococcal agent.

収録刊行物

  • 有機合成化学協会誌

    有機合成化学協会誌 70(3), 265-275, 2012-03-01

    社団法人 有機合成化学協会

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各種コード

  • NII論文ID(NAID)
    10030481778
  • NII書誌ID(NCID)
    AN0024521X
  • 本文言語コード
    JPN
  • 資料種別
    ART
  • ISSN
    00379980
  • NDL 記事登録ID
    023581371
  • NDL 請求記号
    Z17-256
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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