Serendipitous discovery of aryl boronic acids as β-lactamase inhibitors

Shu-Wei Yang; Jianping Pan; Yuriko Root; Giovanna Scapin; Li Xiao; Jing Su

doi:10.1016/j.bmcl.2019.126795

Serendipitous discovery of aryl boronic acids as β-lactamase inhibitors

Bioorg Med Chem Lett. 2020 Jan 15;30(2):126795. doi: 10.1016/j.bmcl.2019.126795. Epub 2019 Nov 9.

Authors

Shu-Wei Yang¹, Jianping Pan¹, Yuriko Root¹, Giovanna Scapin¹, Li Xiao¹, Jing Su²

Affiliations

¹ Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
² Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033, USA. Electronic address: [email protected].

PMID: 31759850
DOI: 10.1016/j.bmcl.2019.126795

Abstract

High throughput screening for β-lactamase inhibitors afforded biphenyl hits such as 1. Hit confirmation and X-ray soaking experiments with Pseudomonas Aeruginosa AmpC enzyme led to the identification of an aryl boronic acid-serine complex 4, which was formed from phenyl boronic acid 8 (an impurity in compound 1) and ethylene glycol (the cryoprotectant in the soaking experiment).

Keywords: Aryl boronic acid; Beta-lactamase inhibitors; Biphenyl; Impurity.

MeSH terms

Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Boronic Acids / chemical synthesis
Boronic Acids / chemistry*
Boronic Acids / metabolism
Drug Design
Pseudomonas aeruginosa / enzymology
beta-Lactamase Inhibitors / chemical synthesis
beta-Lactamase Inhibitors / chemistry*
beta-Lactamase Inhibitors / metabolism
beta-Lactamases / chemistry*
beta-Lactamases / metabolism

Substances

Bacterial Proteins
Boronic Acids
beta-Lactamase Inhibitors
vaborbactam
beta-Lactamases
benzeneboronic acid