Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
School of Chemical Engineering, Chongqing University of Technology, Chongqing 400054, PR China.
Bioorg Med Chem Lett. 2024 May 1;103:129709. doi: 10.1016/j.bmcl.2024.129709. Epub 2024 Mar 15.
A class of unique hydrazyl hydroxycoumarins (HHs) as novel structural scaffold was developed to combat dreadful bacterial infections. Some HHs could effectively suppress bacterial growth at low concentrations, especially, pyridyl HH 7 exhibited a good inhibition against Pseudomonas aeruginosa 27853 with a low MIC value of 0.5 μg/mL, which was 8-fold more active than norfloxacin. Furthermore, pyridyl HH 7 with low hemolytic activity and low cytotoxicity towards NCM460 cells showed much lower trend to induce the drug-resistant development than norfloxacin. Preliminarily mechanism exploration indicated that pyridyl HH 7 could eradicate the integrity of bacterial membrane, result in the leakage of intracellular proteins, and interact with bacterial DNA gyrase via non-covalent binding, and ADME analysis manifested that compound 7 gave good pharmacokinetic properties. These results suggested that the newly developed hydrazyl hydroxycoumarins as potential multitargeting antibacterial agents should be worthy of further investigation for combating bacterial infection.
一类独特的酰腙羟基香豆素（HHs）作为新型结构支架被开发出来以对抗严重的细菌感染。一些 HHs 可以在低浓度下有效抑制细菌生长，特别是吡啶基 HH 7 对铜绿假单胞菌 27853 表现出良好的抑制作用，MIC 值低至 0.5μg/mL，比诺氟沙星活性高 8 倍。此外，吡啶基 HH 7 具有较低的溶血活性和对 NCM460 细胞的细胞毒性，与诺氟沙星相比，诱导耐药发展的趋势要低得多。初步的机制探索表明，吡啶基 HH 7 可以破坏细菌膜的完整性，导致细胞内蛋白质泄漏，并通过非共价结合与细菌 DNA 回旋酶相互作用，ADME 分析表明化合物 7 具有良好的药代动力学特性。这些结果表明，新开发的酰腙羟基香豆素作为潜在的多靶点抗菌剂，值得进一步研究以对抗细菌感染。
