Bioisosteric investigation of ebselen: Synthesis and in vitro characterization of 1,2-benzisothiazol-3(2H)-one derivatives as potent New Delhi metallo-β-lactamase inhibitors

Wen Bin Jin, Chen Xu, Qipeng Cheung, Wei Gao, Ping Zeng, Jun Liu, Edward W.C. Chan, Yun Chung Leung, Tak Hang Chan, Kwok Yin Wong, Sheng Chen, Kin Fai Chan (Corresponding Author)

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9 Citations (Scopus)


Carbapenem-resistant Enterobacteriaceae (CRE) producing New Delhi metallo-β-lactamase (NDM-1) cause untreatable bacterial infections, posing a significant threat to human health. In the present study, by employing the concept of bioisosteric replacement of the selenium moiety of ebselen, we have designed, synthesized and characterized a small compound library of 2-substituted 1,2-benzisothiazol-3(2H)-one derivatives and related compounds for evaluating their cytotoxicity and synergistic activity in combination with meropenem against the E. coli Tg1 (NDM-1) strain. The most promising compound 3a demonstrated potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE strains with FICI as low as 0.09. Moreover, its IC50 value and inhibition mechanism were also confirmed by using the enzyme inhibition assay and the ESI-MS analysis respectively. Importantly, compound 3a has acceptable toxicity and is not a PAINS. Because of its structural simplicity and potent synergistic activity in combination with meropenem, we propose that compound 3a may be a promising meropenem adjuvant and a new series of such compounds may worth further investigations.

Original languageEnglish
Article number103873
JournalBioorganic Chemistry
Publication statusPublished - Jul 2020


  • 1,2-benzisothiazol-3(2H)-one
  • Bioisosteric replacement
  • Carbapenem-resistant Enterobacteriaceae
  • Ebselen
  • New Delhi metallo-β-lactamase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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