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Substituted-amidine derivatives of diazabicyclooctane as prospective β-lactamase inhibitors

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Abstract

Discovery of β-lactamase inhibitors is a continuous process due to inherent capability of resistance in bacteria against existing inhibitors. Diazabicyclooctane ring is a non-β-lactam motif capable of inhibiting the β-lactamases. As part of our efforts, we synthesized a series of diazabicyclooctane derivatives where C2 position of the bicyclic ring is linked with various substituted-amidine moieties. The newly synthesized compounds, alone and in combination with meropenem, were tested against ten bacterial strains for their antibacterial activity in vitro. All compounds did not show antibacterial tendency when tested alone (MIC > 64 mg/dm3) however, showed antibacterial activity in combination with meropenem. All compounds enhanced the potency of meropenem (MIC 2–4 mg/dm3) with MIC values ranging from < 0.125 to 1 mg/dm3 indicating their prospective β-lactamase inhibition capability. One derivative proved to be the most potent among all, and is comparable to avibactam, against eight out of ten bacterial strains.

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Acknowledgements

Authors thank Ministry of Science and Technology, P.R. China for the award of foreign expert program to Dr. Haikang Yang and Dr. Zafar Iqbal. This work was supported by the grant from Science and Technology Department of Ningxia, P.R. China (No. 2018BCG01001).

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Author notes

  1. Yuanbai Liu, Jingwen Ji and Jian Sun contributed equally for this work.

Authors and Affiliations

  1. Ningxia Centre of Organic Synthesis and Engineering Technology, Ningxia Academy of Agriculture and Forestry Sciences No. 590, Huanghe East Road, Jinfeng District, Yinchuan, 750002, Ningxia, People’s Republic of China

    Yuanbai Liu, Jingwen Ji, Jian Sun, Lili He, Yuanyu Gao, Lijuan Zhai, Jinbo Ji, Yangxiu Mu, Dong Tang, Haikang Yang, Zafar Iqbal & Zhixiang Yang

  2. Department of Pharmacy, Ningxia Medical University, Shengli Street, Xingqing District, Yinchuan, 750004, Ningxia, People’s Republic of China

    Xueqin Ma

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  1. Yuanbai Liu
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  2. Jingwen Ji
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  3. Jian Sun
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  4. Lili He
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  10. Dong Tang
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  11. Haikang Yang
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Correspondence to Zafar Iqbal or Zhixiang Yang.

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Liu, Y., Ji, J., Sun, J. et al. Substituted-amidine derivatives of diazabicyclooctane as prospective β-lactamase inhibitors. Monatsh Chem 153, 301–309 (2022). https://doi.org/10.1007/s00706-021-02888-3

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  • DOI: https://doi.org/10.1007/s00706-021-02888-3

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