title: Evolution from a natural flavones nucleus to obtain 2-(4-Propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump.
abstract: Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of substrate antimicrobial agents. Inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant phenotype. In this work, a series of 2-phenyl-4(1H)-quinolone and 2-phenyl-4-hydroxyquinoline derivatives, obtained by modifying the flavone nucleus of known efflux pump inhibitors (EPIs), were synthesized in an effort to identify more potent S. aureus NorA EPIs. The 2-phenyl-4-hydroxyquinoline derivatives 28f and 29f display potent EPI activity against SA-1199B, a strain that overexpresses norA, in an ethidium bromide efflux inhibition assay. The same compounds, in combination with ciprofloxacin, were able to completely restore its antibacterial activity against both S. aureus SA-K2378 and SA-1199B, norA-overexpressing strains.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, 06123 Perugia, Italy. stefano.sabatini@unipg.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Francesca
authors.initials: F
authors.lastname: Gosetto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: Diixa
authors.initials: D
authors.lastname: Patel
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002939:Ciprofloxacin / Q000494:pharmacology; D004357:Drug Synergism; D047309:Flavones / Q000737:chemistry*; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D013045:Species Specificity; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D047309:Flavones; D006912:Hydroxyquinolines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C075040:NorA protein, Staphylococcus; C034010:4-hydroxyquinoline