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

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

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Author(s)

  • 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
  • Kin-Fai Chan

Detail(s)

Original languageEnglish
Pages (from-to)3515-3534
Journal / PublicationNew Journal of Chemistry
Volume45
Issue number7
Online published29 Jan 2021
Publication statusPublished - 21 Feb 2021

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.

Citation Format(s)

Synthesis of 1,3,4-trisubstituted pyrrolidines as meropenem adjuvants targeting New Delhi metallo-β-lactamase. / Jin, Wen Bin; Xu, Chen; Qi, Xiao Lin et al.
In: New Journal of Chemistry, Vol. 45, No. 7, 21.02.2021, p. 3515-3534.

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