title: Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents.
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.
authors.affiliation: Department of Molecular Design for Medicine, Okayama University, Kita-Ku, Okayama 700-8530, Japan.
authors.forename: Abugafar M L
authors.initials: AM
authors.lastname: Hossion
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Zamami
authors.forename: Rafiya K
authors.initials: RK
authors.lastname: Kandahary
authors.forename: Tomofusa
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Wakano
authors.initials: W
authors.lastname: Ogawa
authors.forename: Akimasa
authors.initials: A
authors.lastname: Iwado
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005697:Galactosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011794:Quercetin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D059005:Topoisomerase II Inhibitors
chemical_list: C560273:2-(3',4'-dihydroxyphenyl)-5,7-dihydroxy-3-(2'',6''-di-O-(3'''-(4-fluorophenylpropanoyl)))galactosyl-4H-chromen-4-one; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005697:Galactosides; D059005:Topoisomerase II Inhibitors; D011794:Quercetin; D027101:DNA Topoisomerase IV