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

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• 作者：Emilia Caselli ; Chiara Romagnoli ; Roza Vahabi ; Magdalena A. Taracila ; Robert A. Bonomo ; Fabio Prati
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5445-5458
• 全文大小：544K
• ISSN：1520-4804

文摘

Boronic acid transition-state inhibitors (BATSIs) represent one of the most promising classes of 尾-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鈥揳lkyne 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 尾-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.