RE-EVOLUTION OF THE 2-PHENYL-4-HYDROXYQUINOLINES: OPTIMIZATION OF A POTENT NEW CLASS OF S. AUREUS NorA EFFLUX PUMP INHIBITORS

The current worldwide increase of bacterial resistant strains to almost all the common antibacterials is now considered an alarming health emergency.1 The ability of these microorganisms to develop resistance, makes them insensible to one or more structurally unrelated antibacterials (Multi-Drug Resistance - MDR). Among the strategies by which resistance can be acquired, overexpression of the efflux pumps leads to a sublethal antibacterial concentration at the target that in turn may predispose to the development of high-level target-based resistance. The inhibition of such pumps is thus an important approach for improving the efficacy and/or extending the clinical utility of existing antibiotics, giving new life to old drugs with secure economic, social and health benefit. Of particular concern is the overwhelming rise of methicillinresistant S. aureus (MRSA), that is highly virulent and contagious.2 In S. aureus, the main efflux pump is the NorA protein, which is able to extrude several antibacterials, including hydrophilic fluoroquinolones such as ciprofloxacin, and dyes from the bacterial cell. Taking into account the strong inhibitory activity of NorA efflux pump displayed from some previously reported 2-pheny-4-hydroxylquinoline derivatives,3 in this work we have modified, with the help of computational methods, the less explored C-4 position of the quinoline scaffold, with the aim to improve the inhibitory activity and to complete the information about the SAR of this new class of inhibitors of efflux pump (EPIs). Activity data (Ethidium bromide (EtBr) efflux inhibition and synergistic activity with ciprofloxacin against several S. aureus strains with a different level of NorA pump expression) for the synthesized compounds will be reported.