Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents

Abugafar M L Hossion, Yoshito Zamami, Rafiya K. Kandahary, Tomofusa Tsuchiya, Wakano Ogawa, Akimasa Iwado, Kenji Sasaki

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 μg/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.

Original languageEnglish
Pages (from-to)3686-3703
Number of pages18
JournalJournal of Medicinal Chemistry
Volume54
Issue number11
DOIs
Publication statusPublished - Jun 9 2011
Externally publishedYes

Fingerprint

DNA Topoisomerase IV
DNA Gyrase
Quercetin
Staphylococcus aureus
Vancomycin
Anti-Bacterial Agents
Community-Acquired Infections
Bacterial DNA
Methicillin
Intestinal Absorption
Structure-Activity Relationship
Methicillin-Resistant Staphylococcus aureus
Streptococcus pneumoniae
Molecular Structure
Escherichia coli
Bacteria
Growth
Vancomycin-Resistant Enterococci

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents. / Hossion, Abugafar M L; Zamami, Yoshito; Kandahary, Rafiya K.; Tsuchiya, Tomofusa; Ogawa, Wakano; Iwado, Akimasa; Sasaki, Kenji.

In: Journal of Medicinal Chemistry, Vol. 54, No. 11, 09.06.2011, p. 3686-3703.

Research output: Contribution to journalArticle

Hossion, Abugafar M L ; Zamami, Yoshito ; Kandahary, Rafiya K. ; Tsuchiya, Tomofusa ; Ogawa, Wakano ; Iwado, Akimasa ; Sasaki, Kenji. / Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 11. pp. 3686-3703.
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