title: Click Chemistry in Lead Optimization of Boronic Acids as β-Lactamase Inhibitors.
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 K(i) value of the best compound (13a) was as low as 4 nM with significant reduction of bacterial resistance to the combination of cefotaxime/13a.
authors.affiliation: †Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Caselli
authors.affiliation: †Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Romagnoli
authors.affiliation: †Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
authors.forename: Roza
authors.initials: R
authors.lastname: Vahabi
authors.affiliation: §Departments of Medicine, Pharmacology, Biochemistry, and Molecular Biology and Microbiology, Case Western Reserve University, , Cleveland, Ohio 44106, United States.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Taracila
authors.affiliation: ‡Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States.|§Departments of Medicine, Pharmacology, Biochemistry, and Molecular Biology and Microbiology, Case Western Reserve University, , Cleveland, Ohio 44106, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: †Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Prati
mesh_terms: D001897:Boronic Acids / Q000737:chemistry* / Q000494:pharmacology*; D057930:Click Chemistry; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry; D065093:beta-Lactamase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D014230:Triazoles; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases