Novel Fluoroquinolones With Pinane Moiety: Synthesis and Antimicrobial Activity

Here, we report a synthesis of fluoroquinolones carrying a monoterpene moiety at the C7 position of aromatic structure. The minimal inhibitory concentrations of fluoroquinolone fused with trans-3-hydroxy-cis-myrtanylamine 18 against Staphylococcus aureus (MSSA isolates) were two- to eightfold lower compared to moxifloxacin, although fourfold higher against MRSA isolates. The fluoroquinolone fused with (-)-nopylamine 16 was four- to eightfold less active on MSSA compared to moxifloxacin, while had similar activity on MRSA. Against biofilms, both 16 and 18 were four times more active than both moxifloxacin and ciprofloxacin. Both 16 and 18 induced the drop of membrane potential and in silico exhibited similar binding energies with DNA gyrase of S. aureus (ΔG -13.44 to -13.17 kcal/mol), suggesting dual mechanism of action (topoisomerase inhibition by the fluoroquinolone core and membrane damage by the monoterpene fragment). Thus, our data demonstrate the perspectives of monoterpenes fusion to an antibiotic moiety to obtain dual-acting bipharmacophore antimicrobials with improved activity, including biofilm-associated infections.