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

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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Author(s)

  • 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
  • Kin-Fai Chan

Detail(s)

Original languageEnglish
Article number103873
Journal / PublicationBioorganic Chemistry
Volume100
Online published25 Apr 2020
Publication statusPublished - Jul 2020

Abstract

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. Copyright © 2020 Elsevier Inc. All rights reserved.

Research Area(s)

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

Citation Format(s)

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

In: Bioorganic Chemistry, Vol. 100, 103873, 07.2020.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal