Antimicrobial resistance is a world health problem and with this awareness, some fluoroquinolones are classified for WHO AWaRe as “Watch”, a group with higher resistance potential. Among the known resistance mechanisms, efflux pumps have a relevant role and have been associated with multidrug resistance. Thus, the use of an efflux pump inhibitor may be an approach to restore the antibacterial activity of drugs against pathogens that cause infectious diseases. Phenothiazines have efflux-inhibiting properties and inhibit biofilm formation, which can make them a good antibacterial adjuvant. To attempt a new approach against the antimicrobial resistance of fluoroquinolones, the hybridization of ciprofloxacin and phenothiazines to afford molecules that may display antibacterial and efflux pump inhibitory activities were performed. The hybrid molecules were synthesized using nucleophilic substitution reactions and the characterization of the prepared compounds was mainly performed through nuclear magnetic resonance spectroscopy. Simultaneously, to help understand the interactions of the newly synthesized molecules and the NorA efflux pump, in silico studies were also carried out. The newly synthesized molecules were then evaluated regarding their potential antibacterial activity, by the determination of their minimum inhibitory concentration against NorA wild type Staphylococcus aureus (SA1199) and a NorA overexpressing strain (SA1199B). The results so obtained indicated that some hybrids showed antimicrobial activity even against NorA overexpressing strain. Future work will focus on the evaluation of the mechanisms underlying the antibacterial activity of these new molecules and the potential for restraining resistance development.

This work was developed within the scope of the CICS-UBI projects UIDB/00709/2020 and UIDP/00709/2020, financed by national funds through the Portuguese Foundation for Science and Technology/MCTES. João L. Serrano acknowledges a doctoral fellowship grant from the FCT (SFRH/BD/148028/2019).