Benzopyrone-mediated quinolones as potential multitargeting antibacterial agents.

A new type of benzopyrone-mediated quinolones (BMQs) was rationally designed and efficiently synthesized as novel potential antibacterial molecules to overcome the global increasingly serious drug resistance. Some synthesized BMQs effectively suppressed the growth of the tested strains, outperforming clinical drugs. Notably, ethylidene-derived BMQ 17a exhibited superior antibacterial potential with low MICs of 0.5-2 μg/mL to clinical drugs norfloxacin, it not only displayed rapid bactericidal performance and inhibited bacterial biofilm formation, but also showed low toxicity toward human red blood cells and normal MDA-kb2 cells. Mechanistic investigation demonstrated that BMQ 17a could effectually induce bacterial metabolic disorders and promote the enhancement of reactive oxygen species to disrupt the bacterial antioxidant defense system. It was found that the active molecule BMQ 17a could not only form supramolecular complex with lactate dehydrogenase, which disturbed the biological functions, but also effectively embed into calf thymus DNA, thus affecting the normal function of DNA and achieving cell death. This work would provide an insight into developing new molecules to reduce drug resistance and expand antibacterial spectrum.