Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents

This work identified a class of cyanomethylquinolones
(CQs) and
their carboxyl analogues as potential multitargeting antibacterial
candidates. Most of the prepared compounds showed high antibacterial
activities against most of the tested bacteria, exhibiting lower MIC
values (0.125–2 μg/mL) than those of clinical norfloxacin,
ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance,
and cytotoxicity, as well as good predictive pharmacokinetics of active
CQs and carboxyl analogues revealed their development potential. Furthermore,
they could eradicate the established biofilm, facilitating bacterial
exposure to these antibacterial candidates. These active compounds
could induce bacterial death through multitargeting effects, including
intercalating into DNA, up-regulating reactive oxygen species, damaging
membranes directly, and impeding metabolism. Moreover, the highly
active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings
highlight the potential of CQs and their carboxyl analogues as multitargeting
broad-spectrum antibacterial candidates for treating intractable bacterial
infections.