Pyrimidine-conjugated fluoroquinolones were constructed to cope with the dreadful resistance. Most of the target pyrimidine derivatives effectively suppressed the growth of the tested strains, especially, 4-aminopyrimidinyl compound 1c showed a broad antibacterial spectrum and low cytotoxicity and exhibited superior antibacterial potency against Enterococcus faecalis with a low MIC of 0.25 μg/mL to norfloxacin and ciprofloxacin. The active compound 1c with fast bactericidal potency could inhibit the formation of biofilms and showed much lower trend for the development of drug-resistance than norfloxacin and ciprofloxacin. Further exploration revealed that compound 1c could prompt ROS accumulations in bacterial cells and interact with DNA to form a DNA-1c complex, thus facilitating bacterial death. ADME analysis indicated that compound 1c possessed favorable drug-likeness and promising pharmacokinetic properties. These results demonstrated that pyrimidine-conjugated fluoroquinolones held hope as potential antibacterial candidates and deserve further study.

构建嘧啶结合的氟喹诺酮类药物以应对可怕的耐药性。大多数目标嘧啶衍生物有效抑制了受试菌株的生长，特别是4-氨基嘧啶基化合物1c显示出广谱抗菌谱和低细胞毒性，对粪肠球菌表现出优异的抗菌效力，对诺氟沙星和诺氟沙星的MIC低至0.25 μg/mL。环丙沙星。具有快速杀菌效力的活性化合物1c可以抑制生物膜的形成，并且显示出比诺氟沙星和环丙沙星低得多的耐药性发展趋势。进一步探索发现化合物1c可以促进细菌细胞中活性氧的积累并与DNA相互作用形成DNA- 1c复合物，从而促进细菌死亡。ADME 分析表明，化合物1c具有良好的药物相似性和良好的药代动力学特性。这些结果表明，嘧啶结合的氟喹诺酮类药物有望成为潜在的抗菌候选药物，值得进一步研究。