MISC

2011年6月

Quercetin Diacylglycoside Analogues Showing Dual Inhibition of DNA Gyrase and Topoisomerase IV as Novel Antibacterial Agents

JOURNAL OF MEDICINAL CHEMISTRY
  • Abugafar M. L. Hossion
  • ,
  • Yoshito Zamami
  • ,
  • Rafiya K. Kandahary
  • ,
  • Tomofusa Tsuchiya
  • ,
  • Wakano Ogawa
  • ,
  • Akimasa Iwado
  • ,
  • Kenji Sasaki

54
11
開始ページ
3686
終了ページ
3703
記述言語
英語
掲載種別
DOI
10.1021/jm200010x
出版者・発行元
AMER CHEMICAL SOC

A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6 ''-acylgalactoside, and quercetin 2 '',6 ''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 mu g/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent.

リンク情報
DOI
https://doi.org/10.1021/jm200010x
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000291082500002&DestApp=WOS_CPL
ID情報
  • DOI : 10.1021/jm200010x
  • ISSN : 0022-2623
  • Web of Science ID : WOS:000291082500002

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