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.

Click Chemistry in Lead Optimization of Boronic Acids as β-Lactamase Inhibitors / Caselli, Emilia; Romagnoli, Chiara; Vahabi, Roza; Taracila, Magdalena A; Bonomo, Robert A; Prati, Fabio. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 58:14(2015), pp. 5445-5458. [10.1021/acs.jmedchem.5b00341]

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

CASELLI, Emilia;ROMAGNOLI, Chiara;VAHABI, ROZA;PRATI, Fabio
2015

Abstract

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.
10-lug-2015
58
14
5445
5458
Click Chemistry in Lead Optimization of Boronic Acids as β-Lactamase Inhibitors / Caselli, Emilia; Romagnoli, Chiara; Vahabi, Roza; Taracila, Magdalena A; Bonomo, Robert A; Prati, Fabio. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 58:14(2015), pp. 5445-5458. [10.1021/acs.jmedchem.5b00341]
Caselli, Emilia; Romagnoli, Chiara; Vahabi, Roza; Taracila, Magdalena A; Bonomo, Robert A; Prati, Fabio
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1070085
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