Azetidinimines as a Novel Series of Non-Covalent Broad-Spectrum Inhibitors of β-Lactamases with Submicromolar Activities Against Carbapenemases of Classes A, B and D

Abstract

The increasingly worrisome situation of antimicrobial resistances has pushed synthetic chemists to design original molecules that can fight these resistances. To do so, inhibiting β-lactamases, one of the main modes of resistance to β-lactam antibiotics, is one of the most sought-after strategies, as recently evidenced by the development and approval of avibactam, relabactam and vaborbactam. Yet molecules able to inhibit simultaneously β-lactamases belonging to different molecular classes remain scarce and currently there is no metallo-β-lactamase inhibitor approved for clinical use. Having recently developed a synthetic methodology to access imino-analogues of β-lactams (Chem. – Eur. J. 2017, 23, 12991,see ref) we decided to evaluate them as potential β-lactamase inhibitors and specifically against carbapenemases, which can hydrolyze and inactivate penicillins, cephalosporins and carbapenems. Herein we eport our findings that show that our newly developed family of molecules are indeed excellent β-lactamase inhibitors and that our lead compound can inhibit NDM-1 (0.1 µM), KPC-2 (0.4 µM), and OXA-48 (0.6 µM) even though these three enzymes belong to three different molecular classes of carbapenemases. This lead compound also inhibits the ESBL CTX-M-15 and the cephalosporinase CMY-2, it is metabolically stable, and can repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1.<br><br><br>

Base‐Mediated Generation of Ketenimines from Ynamides: [3+2] Annulation with Azaallyl Anions

“…This reaction, named the Staudinger synthesis, set the template for accessing this particular heterocycle and inspired a myriad of synthetic variations [2] . Our group developed an imino‐variant of this transformation by using an ynamide [3–10] ( 1 a ) to generate in situ [11,12] a highly reactive ketenimine ( 2 a ) [13–15] which can engage in a [2+2] cycloaddition with a diaryl imine ( 3 a ) to give an azetidinimine (Scheme 1a) [16,17] . Exploring this transformation further, we found that when the same reaction conditions were applied to the homologous benzylimine 3 b , the formation of the expected azetidinimine was not observed.…”