Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors

Abstract

Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MβLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC50 value range of 0.032–15.64 μM except 7. The chlorine substituted compounds (1, 2 and 3) inhibited NDM-1 with an IC50 value of less than 0.96 μM, and the fluorine substituted 12 and 13 inhibited VIM-2 with IC50 values of 38.9 and 2.8 μM, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that 9 and 13 are mixed inhibitors for ImiS with Ki values of 0.074 and 0.27μM using imipenem as the substrate. Docking studies showed that 1 and 9, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.

Synthesis and Bioactivity of Thiazolethioacetamides as Potential Metallo-β-Lactamase Inhibitors

“…A possible reason for this is that the kind and position of the substituents in the benzene ring greatly affected the affinity between the inhibitor molecule and MβLs. In line with our previous research [14][15][16][17], electron-absorbing groups have a greater ability to improve the affinity of inhibitors and MβLs. The nitro group has been proven to be an effective zinc ligand in the complex of carboxypeptidase A/aromatic nitropropionic acid [18].…”

“…Antibiotics 2020, 9, 99 2 of 7 design of MβL inhibitors because the sulfur atom can reduce the MβLs activity by binding to the zinc ions which are enzyme active center and replacing the bridging water molecules [12,13]. Recently, our group has reported that thioacetamide derivatives exhibit biological activity which may inhibit MβLs [14][15][16][17]. In addition, some of the thioacetamides showed broad-spectrum inhibitory activity against all three subclasses of MβLs.…”

“…Recently, our group has reported that thioacetamide derivatives exhibit biological activity which may inhibit MβLs [14][15][16][17]. In addition, some of the thioacetamides showed broad-spectrum inhibitory activity against all three subclasses of MβLs.…”

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

“…However, none of them has been clinically approved [ 8 , 15 ]. These are natural plant-based compounds [ 16 , 17 ], synthetic low molecular weight inhibitors [ 10 , 18 , 19 , 20 , 21 , 22 ], β-lactams [ 23 , 24 , 25 , 26 ], amino acid derivatives and peptides [ 27 ]. Boron-based inhibitors attract special attention [ 28 , 29 , 30 ].…”

Binding of 2-(Triazolylthio)acetamides to Metallo-β-lactamase CcrA Determined with NMR

“…Among the previously reported series of diaryl-substituted 2TTAs, ,,− 1–3 were selected for further studies as they showed the highest CcrA inhibitory activity and had a high inhibitory activity against a broad spectrum of MBLs (Table ). Compounds 4–6 showed selectivity for ImiS over CcrA, NDM-1, and L1 .…”