Routes of Synthesis of Carbapenems for Optimizing Both the Inactivation of l,d-Transpeptidase LdtMt1 of Mycobacterium tuberculosis and the Stability toward Hydrolysis by β-Lactamase BlaC

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• 作者：Laura Iannazzo ; Daria Soroka ; Sébastien Triboulet ; Matthieu Fonvielle ; Fabrice Compain ; Vincent Dubée ; Jean-Luc Mainardi ; Jean-Emmanuel Hugonnet ; Emmanuelle Braud ; Michel Arthur ; Mélanie Etheve-Quelquejeu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3427-3438
• 全文大小：609K
• 年卷期：0
• ISSN：1520-4804

文摘

Combinations of β-lactams of the carbapenem class, such as meropenem, with clavulanate, a β-lactamase inhibitor, are being evaluated for the treatment of drug-resistant tuberculosis. However, carbapenems approved for human use have never been optimized for inactivation of the unusual β-lactam targets of Mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum β-lactamase BlaC. Here, we report three routes of synthesis for modification of the two side chains carried by the β-lactam and the five-membered rings of the carbapenem core. In particular, we show that the azide–alkyne Huisgen cycloaddition reaction catalyzed by copper(I) is fully compatible with the highly unstable β-lactam ring of carbapenems and that the triazole ring generated by this reaction is well tolerated for inactivation of the l,d-transpeptidase Ldt_Mt1 target. Several of our new carbapenems are superior to meropenem both with respect to the efficiency of in vitro inactivation of Ldt_Mt1 and reduced hydrolysis by BlaC.