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

• Published in: Bioorganic chemistry 2020-07, Vol.100, p.103873-103873, Article 103873
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 1,2-benzisothiazol-3(2H)-one; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Azoles - chemical synthesis; Azoles - chemistry; Azoles - pharmacology; beta-Lactamase Inhibitors - chemical synthesis; beta-Lactamase Inhibitors - chemistry; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - metabolism; Bioisosteric replacement; Carbapenem-resistant Enterobacteriaceae; Ebselen; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - metabolism; Humans; Molecular Docking Simulation; New Delhi metallo-β-lactamase inhibitors; Organoselenium Compounds - chemical synthesis; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacology; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103873

[Display omitted] •A compound library of 1,2-benzisothiazol-3(2H)-one derivatives was constructed.•Compound 3a demonstrates promising synergism against NDM-1 positive CRE strains.•Both IC50 and inhibition mechanisms of 3a towards the NDM-1 were also confirmed. 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.