Synthesis of 1,3,4-trisubstituted pyrrolidines as meropenem adjuvants targeting New Delhi metallo-β-lactamase

Wen Bin Jin, Chen Xu, Xiao Lin Qi, Ping Zeng, Wei Gao, Ki Hon Lai, Jiachi Chiou, Edward W.C. Chan, Yun Chung Leung, Tak Hang Chan, Kwok Yin Wong, Sheng Chen (Corresponding Author), Kin Fai Chan (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

1 Citation (Scopus)

Abstract

The effective strategies to neutralize the New Delhi metallo-β-lactamase (NDM-1) activity offer unique opportunities to combination therapy because NDM-1 inactivates all classes of carbapenem antibiotics, which are widely regarded as the last resort of drugs for treating serious bacterial infections. Here we describe the efficient construction of a series of trans-1,3,4-trisubstituted pyrrolidines via boric acid-catalyzed 1,3-dipolar cycloaddition of N-benzylazomethine ylide with methyl ferulate for the biological evaluation of their cytotoxicity and synergistic activity in combination with meropenem towards NDM-1 positive carbapenem-resistant Enterobacteriaceae (CRE). The cell-based screens generated one promising hit, namely compound 10e, which exhibited low cytotoxicity (IC50 > 128 μM), moderate NDM-1 enzyme inhibition (IC50 = 51 μM), and potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE with fractional inhibitory concentration indexes ranging from 0.01 to 0.25. Structure-activity relationship studies revealed that the zinc-chelating moiety of 2-(bis(pyridin-2-ylmethyl)-amino)acetyl group of compound 10e plays a pivotal role for potent activity. Regarding the inhibition mechanism, a series of biochemical assays revealed that compound 10e may inactivate NDM-1 activity by displacing both zinc ions from the active site of the enzyme. Altogether, our studies indicate that compound 10e represents an important pyrrolidine-type scaffold targeting NDM-1, providing a promising starting point to be further developed as carbapenem antibiotic adjuvants. This journal is

Original languageEnglish
Pages (from-to)3515-3534
Number of pages20
JournalNew Journal of Chemistry
Volume45
Issue number7
DOIs
Publication statusPublished - 21 Feb 2021

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Materials Chemistry

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