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

Xin-Miao Wu; Ling-Yun Li; Xiao-Han Wu; Jin-Xin Wang; Shao-Lin Zhang; Peng-Li Zhang; Cheng-He Zhou

doi:10.1016/j.bioorg.2026.110076

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

Bioorg Chem. 2026 Jun 9:180:110076. doi: 10.1016/j.bioorg.2026.110076. Online ahead of print.

Authors

Xin-Miao Wu¹, Ling-Yun Li¹, Xiao-Han Wu¹, Jin-Xin Wang², Shao-Lin Zhang³, Peng-Li Zhang⁴, Cheng-He Zhou⁵

Affiliations

¹ Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
² Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China; Chongqing Werlchem New Materials Technology Co., Ltd, Chongqing 401120, China. Electronic address: wangjinxin@email.swu.edu.cn.
³ School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, China. Electronic address: zhangsl@cqu.edu.cn.
⁴ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China. Electronic address: zhangpengli@zidd.ac.cn.
⁵ Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China. Electronic address: zhouch@swu.edu.cn.

PMID: 42284880
DOI: 10.1016/j.bioorg.2026.110076

Abstract

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.

Keywords: Antibacterial; Multitargeting antibacterial mechanisms; Naphthalimide; Nitroimidazolyl ethylalcohol; Resistance.