Discovery of novel structural imidazolylvinylquinolones exerting excellent broad-spectrum antibacterial efficacy with multitargeting potential.

A unique type of imidazolylvinylquinolones (IVQs) as novel structural scaffold were developed which afforded excellent broad-spectrum antibacterial efficacy with multitargeting potential. Most of the prepared IVQs gave high antibacterial activity and broad antibacterial spectrum, and especially ethyl IVQ 14a, in which the ethyl group was the most suitable fragment among all the investigated substituents to perform the most effective biosupramolecular effect, showed potent antibacterial activity against MRSA (MIC = 0.25 μg/mL), with an enhanced efficacy 16-fold that of ciprofloxacin. Molecule 14a also demonstrated low drug resistance, hemolysis, and cytotoxicity, and rapidly bactericidal ability. Mechanism evaluation revealed that molecule 14a could not only interfere with membranous function and form DNA-14a supramolecular complex by intercalation that might obstruct DNA replication, but also effectively interact with lactate dehydrogenase via hydrogen bonds which could obstruct the function of enzyme and inhibit bacterial metabolism, thereby exerting potent bactericidal effect. These potential multitargeting antibacterial actions enabled ethyl IVQ 14a to exhibit stronger anti-MRSA efficacy without the obvious development of bacterial resistance than ciprofloxacin in vivo. This series of medicinal chemobiological evaluation towards the topic compounds strongly suggested the development potential of unique imidazolylvinylquinolones as novel structural scaffold to combat bacterial resistance.