Click Chemistry in Lead Optimization of Boronic Acids as β‑Lactamase Inhibitors

Boronic
acid transition-state inhibitors (BATSIs) represent one
of the most promising classes of β-lactamase inhibitors. Here
we describe a new class of BATSIs, namely, 1-amido-2-triazolylethaneboronic
acids, which were synthesized by combining the asymmetric homologation
of boronates with copper-catalyzed azide–alkyne cycloaddition
for the stereoselective insertion of the amido group and the regioselective
formation of the 1,4-disubstituted triazole, respectively. This synthetic
pathway, which avoids intermediate purifications, proved to be flexible
and efficient, affording in good yields a panel of 14 BATSIs bearing
three different R1 amide side chains (acetamido, benzylamido, and
2-thienylacetamido) and several R substituents on the triazole. This
small library was tested against two clinically relevant class C β-lactamases
from Enterobacter spp. and Pseudomonas aeruginosa. The Ki value of the best compound (13a) was as low
as 4 nM with significant reduction of bacterial resistance to the
combination of cefotaxime/13a.