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>

1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity

“…More recently, appeared several families of inhibitors active on both SBLs and MBLs including boronates [26][27][28][29], phosphonates [30] and azetidinimines [31]. Only few compounds are currently promising [32].…”

Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

“…Nonetheless, there are moderate cytotoxic effects indicated by an IC 50 value of 19.9 μM against the MRC-5 cell line and 32.3 μM against the HCT-116 cell line. 17 A derivative of phosphonamidate, (R/S)-(2-(methoxy(methyl(pyridin-2-ylmethyl)amino)phosphoryl)ethyl) ethanethioate (S18), inhibited NDM-1 quantitatively with an IC 50 value of 356 μM. In combination, S18-meropenem neither showed a significant inhibitory effect on the E. coli strain expressing NDM-1 nor potential to restore meropenem activity.…”

“…15 The carbapenemases, notably, the New Delhi MBL (NDM), imipenemase (IMP), Verona integron-encoded MBL (VIM), Klebsiella pneumonia carbapenemase (KPC) and OXA-48, a D class carbapenemase, represent the critically implicated bacterial enzymes in AR pathogenesis. [16][17][18] They are responsible for the worst ARrelated clinical conditions, but to date, there are no approved inhibitors, making this an urgent issue to be addressed. The available antibiotics, specifically the most active β-lactamtypes, are subjected to deactivation by the notorious enzymes through the opening of their β-lactam rings and deacetylation of their corresponding complexes with the enzymes.…”

Synthesis of β-Lactams through Carbonylation of Diazo Compounds Followed by the [2 + 2] Cycloaddition Reaction

“…mp: 134−135 °C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.83 (d, J = 7.1 Hz, 2H), 7.44 (t, J = 7.3 Hz, 2H), 7.42−7.32 (m, 2H), 7.30 (dd, J = 6.2, 4.3 Hz, 4H), 7.13−7.06 (m, 1H), 6.99 (ddd, J = 10.7, 8.6, 2.4 Hz, 1H), 6.86 (t, J = 8.1 Hz, 1H), 5.72 (s, 1H), 3.37 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 167.2 (s), 161.7 (s), 136.1 (s), 133.9 (s), 129.4 (s), 128.9 (s), 128.8 (s), 128.3 (d, J = 52.6 Hz), 127.6 (d, J = 2.7 Hz), 124.8 (s), 117.5 (d, J = 3.6 Hz), 117.3 (s), 111.9 (d, J = 3.7 Hz), 111.7 (d, J = 3.6 Hz), 104.6 (t, J = 25.3 Hz), 104.6 (s), 73 Methyl (3R,4S)-1-(4-Bromophenyl)-2-oxo-3,4-diphenylazetidine-3-carboxylate (4g). Purified by column chromatography (hexane/ Et 2 O 95:5).…”

“…13 C{1 H} NMR (100 MHz, CDCl 3 ) 166.6 (s), 161.9 (s), 136.9 (s), 135.1 (s), 134.6 (s), 132.5 (s), 129.3 (s), 129.2 (s), 128.9 (s), 128.7 (s), 128.6 (s), 127.6 (s), 124.6 (s), 117.4 (s),73.2 (s), 65.6 (s), 62.0 (s), 13.7 (s). IR (film): 3055, 2984, 1763, 1724, 1601, 1501, 1380, 1253, 1088, 1006, 753, 688 cm −1 .…”