Boronic acid transition state inhibitors (BATSIs) represent one of the most promising class of β-lactamase inhibitors. Here we describe a new class of BATSIs, namely 1-amido-2-triazolylethaneboronic acids, which were synthesized combining the asymmetric homologation of boronates with Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) 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 fourteen 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.
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