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.

Investigation on the effect of known potent S. aureus NorA efflux pump inhibitors on the staphylococcal biofilm formation

“…Furthermore, the few known NorA EPIs differ in terms of shape and structure and to date their mechanism of action has not been fully claried. Anyway, given our experience in the design and synthesis of NorA EPIs, [31][32][33][34] in this work we investigated the capability of previously reported potent NorA EPIs 32-34 to inhibit biolm formation in different Staphylococcus strains. To the best of our knowledge, few examples of biolm formation inhibition by EPIs in S. aureus have been reported so far, and, in any case, they concern the use of known and toxic compounds such as CCCP and TZ.…”

“…The MICs of the four NorA EPIs (the 2-phenylquinolines 1a-c 32,33 and the pyrazolobenzothiazine 2 34 Fig. 1) and TZ were rstly determined on S. aureus (ATCC 29213) and S. epidermidis (ATCC 35984).…”

“…To evaluate if the NorA efflux pump inhibition could inuence the biolm formation of S. aureus and S. epidermidis, biolms were grown in the absence or presence of NorA EPIs (1a-c 32,33 and 2) 34 and TZ at different concentrations (250, 125, 62.5, 25 and 2.5 mg mL À1 ) and the biolm mass was analysed by Cristal…”

“…Thus, with the aim to nd dual EP-biolm formation inhibitors, we selected four of the in house most potent NorA EPIs (three 2-phenylquinolines 1a-c 32,33 and a pyrazolobenzothiazine 2 34 Fig. 1), in order to assess their ability to inhibit biolm formation and/or induce biolm dispersal on S. aureus (ATCC 29213) and S. epidermidis (ATCC 35984).…”

(5-Chloroquinolin-8-yl)-2-fluorobenzoate. The Halogen Bond as a Structure Director

“…The N-heterocycles such as quinolines are important starting pharmacophores for preparing therapeutic agents with a wide spectrum of biological activities, such as antimalarial [1], antiviral [2], antibacterial [3], anti-inflammatory [4], and mainly antitumor [5][6][7] activities. The incorporation of diverse halogen atoms into their structures, especially chlorine and fluorine, can lead to important changes in their chemical, pharmacological and physical properties [8][9][10].…”