Discovery of 3-aryl substituted benzoxaboroles as broad-spectrum inhibitors of serine- and metallo-β-lactamases.

Bioorg Med Chem Lett

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address:

Published: June 2021

AI Article Synopsis

  • The production of β-lactamases is a key factor in the resistance to important β-lactam antibiotics, leading to a growing need for effective inhibitors.
  • Boron-containing compounds have shown potential as broad-spectrum inhibitors against these β-lactamases.
  • A specific compound, 9f, exhibited strong inhibitory activity against KPC-2 SBL and reduced the effectiveness of meropenem against resistant bacterial strains, with minimal toxicity observed in human cells.

Article Abstract

The production of β-lactamases represents the main cause of resistance to clinically important β-lactam antibiotics. Boron containing compounds have been demonstrated as promising broad-spectrum β-lactamase inhibitors to combat β-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which manifested broad-spectrum inhibition to representative serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs). The most potent inhibitor 9f displayed an IC value of 86 nM to KPC-2 SBL and micromolar inhibitory activity towards other tested enzymes. Cell-based assays further revealed that 9f was able to significantly reduce the MICs of meropenem in clinically isolated KPC-2-producing bacterial strains and it showed no apparent toxicity in HEK293T cells.

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Source
http://dx.doi.org/10.1016/j.bmcl.2021.127956DOI Listing

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