Naphthalimide-mediated multitargeting antibacterial actions to enhance efficacy and broaden antibacterial spectrum of nitroimidazolyl ethylalcohols.

To combat the escalating challenge of bacterial resistance, a novel class of naphthalimide-mediated nitroimidazolyl ethylalcohols (NNEs) was developed. Most of the prepared NNEs showed potent antibacterial activities. Notably, nitrophenylamino NNE 37 g enhanced the activity of metronidazole against anaerobic bacteria and expanded its antibacterial spectrum to aerobic bacteria (MICs = 0.25-4 μg/mL), being superior to ciprofloxacin and ceftizoxime. Structure-activity relationship analysis suggested that the nitroimidazolyl ethylalcohol fragment was essential for activity, whereas chirality showed negligible effect on antibacterial efficacy. NNE 37 g also demonstrated low cytotoxicity, hemolysis, drug resistance and favorable plasma stability. Galleria mellonella infection model further demonstrated its more potent anti-MRSA efficacy in vivo than ciprofloxacin. Moreover, NNE 37 g displayed multitargeting antibacterial mechanisms, involving allosteric inhibition of PBP2a, DNA intercalation, and disruption of redox homeostasis via ROS/RNS overproduction, ultimately resulting in bacterial cell death. This series of studies provides a promising prospect for the development of naphthalimide-mediated nitroimidazolyl ethylalcohols as potential antibacterial candidates to tackle bacterial infections.