New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

New antibacterial 3-(aminothiazolyl)quinolones (ATQs) were designed and efficiently synthesized to counteract the growing multidrug resistance in animal husbandry. Bioactive assays manifested that N,N-dicyclohexylaminocarbonyl ATQ 10e and methyl ATQ 17a, respectively, showed better antibacterial behavior against Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa than reference drug norfloxacin. Notably, highly active ATQ 17a with low hemolysis, negligible mammalian cytotoxicity, and good pharmacokinetic properties displayed low trends to induce resistance and synergistic combinations with norfloxacin. Preliminary mechanism exploration implied that representative ATQ 17a could inhibit the formation of biofilms and destroy bacterial membrane integrity, further binding to intracellular DNA and DNA gyrase to hinder bacterial DNA replication. ATQ 17a could also induce the production of excess reactive oxygen species and reduce bacterial metabolism to accelerate bacterial death. These results provided a promise for 3-(aminothiazolyl)quinolones as new potential multitargeting antibacterial agents to treat bacterial infection of animals.

Automated summary

New antibacterial 3-(aminothiazolyl)quinolones were synthesized to combat multidrug resistance in animal husbandry. Bioactive assays showed that N,N-dicyclohexylaminocarbonyl ATQ 10e and methyl ATQ 17a exhibited better antibacterial behavior against Staphylococcus aureus and Pseudomonas aeruginosa than norfloxacin. Mechanism exploration indicated that ATQ 17a could inhibit biofilm formation, disrupt bacterial membrane integrity, bind to intracellular DNA and DNA gyrase, induce reactive oxygen species production, and reduce bacterial metabolism.