Discovery of natural berberine-derived nitroimidazoles as potentially multi-targeting agents against drug-resistant Escherichia coli  

作　　者：Guo-Biao Zhang Swetha Kameswari Maddili Vijai Kumar Reddy Tangadanchu Lavanya Gopala Wei-Wei Gao Gui-Xin Cai Cheng-He Zhou 

机构地区：[1]Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University

出　　处：《Science China Chemistry》2018年第5期557-568,共12页中国科学（化学英文版）

基　　金：supported by the National Natural Science Foundation of China(21672173,21372186);Research Fund for International Young Scientists from International(Regional)Cooperation and Exchange Program of NSFC(81650110529);Chongqing Special Foundation for Postdoctoral Research Proposal(Xm2016039,Xm2017185);Program for Overseas Young Talents from State Administration of Foreign Experts Affairs,China(WQ2017XNDX047);the Doctoral Fund of Southwest University(SWU111075);the Research Funds for the Central Universities(XDJK2017B015)

摘　　要：A series of natural berberine-derived nitroimidazoles as novel antibacterial agents were designed, synthesized and characterized by nuclear magnetic resonance(NMR), infrared spectra(IR), and high resolution mass spectra(HRMS) spectra. The antimicrobial evaluation showed that some target molecules exhibited moderate to good inhibitory activities against the tested bacteria and fungi including clinical drug-resistant strains isolated from infected patients. Especially, 2-fluorobenzyl derivative8 f not only gave strong activity against drug-resistant E. coli with the minimal inhibitory concentration(MIC) value of0.003 m M, 33-fold more active than norfloxacin, but also exhibited low toxicity toward RAW 264.7 cells and less propensity to trigger resistance. The aqueous solubility and Clog P values of target compounds were investigated to elucidate the structureactivity relationships. Molecular docking and quantum chemical studies for compound 8 f rationally explained its antibacterial effect. The further exploration of antibacterial mechanism revealed that the highly active compound 8 f could effectively permeabilize E. coli cell membrane and intercalate into DNA isolated from resistant E. coli to form 8 f-DNA complex that might block DNA replication to exert the powerful bioactivities. Compound 8 f could also selectively address resistant E. coli from a mixture of various strains.A series of natural berberine-derived nitroimidazoles as novel antibacterial agents were designed, synthesized and characterized by nuclear magnetic resonance（NMR）, infrared spectra（IR）, and high resolution mass spectra（HRMS） spectra. The antimicrobial evaluation showed that some target molecules exhibited moderate to good inhibitory activities against the tested bacteria and fungi including clinical drug-resistant strains isolated from infected patients. Especially, 2-fluorobenzyl derivative8 f not only gave strong activity against drug-resistant E. coli with the minimal inhibitory concentration（MIC） value of0.003 m M, 33-fold more active than norfloxacin, but also exhibited low toxicity toward RAW 264.7 cells and less propensity to trigger resistance. The aqueous solubility and Clog P values of target compounds were investigated to elucidate the structureactivity relationships. Molecular docking and quantum chemical studies for compound 8 f rationally explained its antibacterial effect. The further exploration of antibacterial mechanism revealed that the highly active compound 8 f could effectively permeabilize E. coli cell membrane and intercalate into DNA isolated from resistant E. coli to form 8 f-DNA complex that might block DNA replication to exert the powerful bioactivities. Compound 8 f could also selectively address resistant E. coli from a mixture of various strains.

关 键 词：berberine nitroimidazole Escherichia coli DNA membrane permeabilization 

分 类 号：TQ460.1[化学工程—制药化工] F279.241[经济管理—企业管理]