Design and Synthesis of 3-Hydroxy-pyridin-4(1H)-ones–Ciprofloxacin Conjugates as Dual Antibacterial and Antibiofilm Agents against Pseudomonas aeruginosa,Journal of Medicinal Chemistry

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Design and Synthesis of 3-Hydroxy-pyridin-4(1H)-ones–Ciprofloxacin Conjugates as Dual Antibacterial and Antibiofilm Agents against Pseudomonas aeruginosa
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-01-24 , DOI: 10.1021/acs.jmedchem.2c02044
Yuan-Yuan Wang ₁ , Xiao-Yi Zhang ₁ , Xiao-Lin Zhong ₁ , Yong-Jun Huang ₁ , Jing Lin ₁ , Wei-Min Chen ₁

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Pseudomonas aeruginosa infections are often complicated by the fact that it can easily form a biofilm that increases its resistance to antibiotics. Consequently, the development of novel antibacterial agents against biofilm-associated drug-resistant P. aeruginosa is urgently needed. Herein, we report a series of 3-hydroxy-pyridin-4(1H)-ones–ciprofloxacin conjugates that were designed and synthesized as dual antibacterial and antibiofilm agents against P. aeruginosa. A potential 2-substituted 3-hydroxy-1,6-dimethylpyridin-4(1H)-one–ciprofloxacin conjugate (5e) was identified and had the best minimum inhibitory concentrations of 0.86 and 0.43 μM against P. aeruginosa 27853 and PAO1 and reduced 78.3% of biofilm formation. In addition, 5e eradicates mature biofilms and kills living bacterial cells that are incorporated into the biofilm. Studies on the antibiofilm mechanism of conjugates showed that 5e interferes with iron uptake by bacteria, inhibits their motility, and reduces the production of virulence. These results demonstrate that 3-hydroxy-pyridin-4(1H)-ones–ciprofloxacin conjugates are potent in the treatment of biofilm-associated drug-resistant P. aeruginosa infections.

中文翻译：

3-Hydroxy-pyridin-4(1H)-ones-Ciprofloxacin 偶联物的设计与合成作为抗铜绿假单胞菌的双重抗菌和抗生物膜剂

铜绿假单胞菌感染通常很复杂，因为它很容易形成生物膜，增加其对抗生素的耐药性。因此，迫切需要开发针对生物膜相关耐药铜绿假单胞菌的新型抗菌剂。在此，我们报告了一系列 3-hydroxy-pyridin-4(1 H )-ones-ciprofloxacin 结合物，它们被设计和合成为针对铜绿假单胞菌的双重抗菌和抗生物膜剂。鉴定了一种潜在的 2-取代 3-羟基-1,6-二甲基吡啶-4(1 H )-酮-环丙沙星偶联物 ( 5e )，其对铜绿假单胞菌的最佳最低抑制浓度分别为 0.86 和 0.43 μM27853 和 PAO1 并减少了 78.3% 的生物膜形成。此外，5e根除成熟的生物膜并杀死并入生物膜的活细菌细胞。对偶联物抗生物膜机制的研究表明，5e会干扰细菌对铁的吸收，抑制它们的运动，并降低毒力的产生。这些结果表明 3-hydroxy-pyridin-4(1 H )-ones-ciprofloxacin 偶联物可有效治疗生物膜相关的耐药铜绿假单胞菌感染。

更新日期：2023-01-24

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