The thiopyranopyridine moiety was synthesized as a new heterocyclic base to be inserted at the C-7 position of selected quinolone nuclei followed by a determination of antibacterial activity against strains of Staphylococcus aureus. Selected thiopyranopyridinylquinolones showed significant antimicrobial activity, including strains having mutations in gyrA and grlA as well as other strains overexpressing the NorA multidrug (MDR) efflux pump. Most derivatives did not appear to be NorA substrates. The effect of the thiopyranopyridinyl substituent on making these quinolones poor substrates for NorA was investigated further. Several quinolone ester intermediates, devoid of any intrinsic antibacterial activity, were tested for their abilities to inhibit the activities of NorA (MFS family) and MepA (MATE family) S. aureus MDR efflux pumps. Selected quinolone esters were capable of inhibiting both MDR pumps more efficiently than the reference compound reserpine. Moreover, they also were able to restore, and even enhance, the activity of ciprofloxacin toward some genetically modified resistant S. aureus strains. © 2010 American Chemical Society.

From 6-aminoquinolone antibacterials to 6-amino-7- thiopyranopyridinylquinolone ethyl esters as inhibitors of staphylococcus aureus multidrug efflux pumps / Pieroni, Marco; Dimovska, Mirjana; Brincat, Jean Pierre; Sabatini, Stefano; Carosati, Emanuele; Massari, Serena; Kaatz, Glenn W.; Fravolini, Arnaldo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:11(2010), pp. 4466-4480. [10.1021/jm1003304]

From 6-aminoquinolone antibacterials to 6-amino-7- thiopyranopyridinylquinolone ethyl esters as inhibitors of staphylococcus aureus multidrug efflux pumps

PIERONI, Marco;
2010

Abstract

The thiopyranopyridine moiety was synthesized as a new heterocyclic base to be inserted at the C-7 position of selected quinolone nuclei followed by a determination of antibacterial activity against strains of Staphylococcus aureus. Selected thiopyranopyridinylquinolones showed significant antimicrobial activity, including strains having mutations in gyrA and grlA as well as other strains overexpressing the NorA multidrug (MDR) efflux pump. Most derivatives did not appear to be NorA substrates. The effect of the thiopyranopyridinyl substituent on making these quinolones poor substrates for NorA was investigated further. Several quinolone ester intermediates, devoid of any intrinsic antibacterial activity, were tested for their abilities to inhibit the activities of NorA (MFS family) and MepA (MATE family) S. aureus MDR efflux pumps. Selected quinolone esters were capable of inhibiting both MDR pumps more efficiently than the reference compound reserpine. Moreover, they also were able to restore, and even enhance, the activity of ciprofloxacin toward some genetically modified resistant S. aureus strains. © 2010 American Chemical Society.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2822816
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