Hydroxamates as a potent skeleton for the development of metallo‐β‐lactamase inhibitors

Abstract

Bacterial resistance caused by metallo-βlactamases (MβLs) has become an emerging public health threat, and the development of MβLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O-aryloxycarbonyl hydroxamates were constructed and assayed against MβLs. The obtained molecules specifically inhibited imipenemase-1 (IMP-1) and New Delhi metallo-βlactamase-1, exhibiting an IC 50 value in the range of 0.10-18.42 and 0.23-22.33 μM, respectively. The hydroxamate 5 was found to be the most potent inhibitor, with an IC 50 of 0.1 and 0.23 μM using meropenem and cefazolin as substrates. ICP-MS analysis showed that 5 did not coordinate to the Zn(II) ions at the active site of IMP-1, while the rapid dilution, thermal shift and MALDI-TOF assays revealed that the hydroxamate formed a covalent bond with the enzyme. Cytotoxicity assays indicated that the hydroxamates have low toxicity in MCF-7 cells. This work provided a potent scaffold for the development of MβLs inhibitors.

Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

“…The FRET experiments were performed to screen the potential M pro inhibitors [28] , [29] . The hydroxamates and thiosemicarbazones were prepared in our lab, characterized by 1 H and 13 C NMR, confirmed by HRMS, and reported to be the inhibitors of metallo-β-lactamases [26] , [27] ( Fig. 2 ).…”

“…As the NDM-1 inhibitors, the Ebsulfur and Ebselen were reported to inhibit M pro [25] . Recently, both hydroxamates and thiosmicarbazones were synthesized in our lab and characterized by NMR and mass spectrometry and evaluated to have inhibitory efficacy on NDM-1 [26] , [27] . In the same case, we expected these two classes of compounds to have inhibitory activity on M pro , therefore evaluated them.…”

Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding

“…1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.92 (s, 1H), 7.37−7.27 (m, 5H), 7.05 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.50 (s, 2H), 4.23 (s, 2H) ppm. 13 (27). A suspension of 13d (327 mg, 1.00 mmol), 4-pyridylboronic acid (366 mg, 3.00 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol), and cesium carbonate (978 mg, 3.00 mmol) in 1,4-dioxane was stirred for 4 h at 110 °C under argon.…”

“…The title compound was prepared in a manner similar to that for compound 23,15% yield for five steps, 97.4% HPLC purity. 1 (27). A suspension of 13d (327 mg, 1.00 mmol), 4-pyridylboronic acid (366 mg, 3.00 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol), and cesium carbonate (978 mg, 3.00 mmol) in 1,4-dioxane was stirred for 4 h at 110 °C under argon.…”

“…MBLs are zinc-dependent metalloenzymes, which utilize Zn­(II)-bound hydroxyl for β-lactam hydrolysis . Various inhibitor chemotypes have been reported to target MBLs, − which can be broadly classified as type I–V inhibitors based on the proposed mechanisms of MBL-mediated β-lactam hydrolysis (Figure ). The potent and broad-spectrum MBL inhibitors typically achieve their efficacy by mimicking key features of complexes involved in β-lactam binding and reactions, albeit at different phases of catalysis. , Currently, three drug candidates, namely VNRX-5133 (taniborbactam), QPX7728 (xeruborbactam), and QPX7831, which are dual MBL/SBL inhibitors, are undergoing evaluation in clinical trials.…”