Li Zhen-Zhen, Gopala Lavanya, Tangadanchu Vijai Kumar Reddy, Gao Wei-Wei, Zhou Cheng-He
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
Bioorg Med Chem. 2017 Dec 15;25(24):6511-6522. doi: 10.1016/j.bmc.2017.10.028. Epub 2017 Oct 25.
A series of nitroimidazole enols as new bacterial DNA-targeting agents were for the first time designed, synthesized and characterized by NMR, IR and HRMS spectra. The antimicrobial screening revealed that 2-methoxyphenyl nitroimidazole enol 3i possessed stronger anti-P. aeruginosa efficacy (MIC = 0.10 μmol/mL) than reference drugs Norfloxacin and Metronidazole. Time-kill kinetic assay manifested that the active molecule 3i could rapidly kill the tested strains. Molecular docking indicated that the interactions between compound 3i and topoisomerase II were driven by hydrogen bonds. Quantum chemical study was also performed on 3i to understand the structural features essential for activity. Further research found that compound 3i was not able to effectively intercalate into bacterial DNA but could cleave DNA isolated from the standard P. aeruginosa strain, which might block DNA replication to exert the efficient bioactivities, and this active molecule was also able to be stored and carried by human serum albumin via hydrophobic interactions and hydrogen bonds.
首次设计、合成了一系列作为新型细菌DNA靶向剂的硝基咪唑烯醇，并通过核磁共振光谱、红外光谱和高分辨质谱对其进行了表征。抗菌筛选显示，2-甲氧基苯基硝基咪唑烯醇3i对铜绿假单胞菌的抗菌效果（最低抑菌浓度MIC = 0.10 μmol/mL）比参考药物诺氟沙星和甲硝唑更强。时间杀菌动力学试验表明，活性分子3i能迅速杀死受试菌株。分子对接表明，化合物3i与拓扑异构酶II之间的相互作用是由氢键驱动的。还对3i进行了量子化学研究，以了解其活性所必需的结构特征。进一步研究发现，化合物3i不能有效地插入细菌DNA，但能切割从标准铜绿假单胞菌菌株分离的DNA，这可能会阻断DNA复制以发挥有效的生物活性，并且这种活性分子还能够通过疏水相互作用和氢键与人血清白蛋白结合并被其携带。
