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

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Abstract

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.

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Acknowledgements

This work was partially 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), and the Research Funds for the Central Universities (XDJK2017B015).

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Authors and Affiliations

  1. Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China

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

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  1. Guo-Biao Zhang
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  2. Swetha Kameswari Maddili
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  3. Vijai Kumar Reddy Tangadanchu
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  4. Lavanya Gopala
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  5. Wei-Wei Gao
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  6. Gui-Xin Cai
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  7. Cheng-He Zhou
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Correspondence to Gui-Xin Cai or Cheng-He Zhou.

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11426_2017_9169_MOESM1_ESM.pdf

Discovery of Natural Berberine-derived Nitroimidazoles as Potentially Multi-targeting Agents against Drug-resistant Escherichia coli

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Zhang, GB., Maddili, S.K., Tangadanchu, V.K.R. et al. Discovery of natural berberine-derived nitroimidazoles as potentially multi-targeting agents against drug-resistant Escherichia coli. Sci. China Chem. 61, 557–568 (2018). https://doi.org/10.1007/s11426-017-9169-4

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