LAUSR

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 derivative 8f not only gave strong activity against drug-resistant E. coli with the minimal inhibitory concentration (MIC) value of 0.003 mM, 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 ClogP values of target compounds were investigated to elucidate the structureactivity relationships. Molecular docking and quantum chemical studies for compound 8f rationally explained its antibacterial effect. The further exploration of antibacterial mechanism revealed that the highly active compound 8f could effectively permeabilize E. coli cell membrane and intercalate into DNA isolated from resistant E. coli to form 8f-DNA complex that might block DNA replication to exert the powerful bioactivities. Compound 8f could also selectively address resistant E. coli from a mixture of various strains.