Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents

作者：Yi-Min Tan, Jing Zhang, Yu-Jia Wei, Yue-Gao Hu, Shu-Rui Li, Shaolin Zhang, Cheng‐He Zhou · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c00238 · 被引用次数：40 · 研究领域：Phenothiazines and Benzothiazines Synthesis and Activities、Synthesis and biological activity、Cancer therapeutics and mechanisms

This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125–2 μg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance, and cytotoxicity, as well as good predictive pharmacokinetics of active CQs and carboxyl analogues revealed their development potential. Furthermore, they could eradicate the established biofilm, facilitating bacterial exposure to these antibacterial candidates. These active compounds could induce bacterial death through multitargeting effects, including intercalating into DNA, up-regulating reactive oxygen species, damaging membranes directly, and impeding metabolism. Moreover, the highly active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings highlight the potential of CQs and their carboxyl analogues as multitargeting broad-spectrum antibacterial candidates for treating intractable bacterial infections.