Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

Zhai, Le; Zhang, Yilin; Kang, Joon S.; Oelschlaeger, Peter; Xiao, Lin; Nie, Sha-Sha; Yang, Ke‐Wu

doi:10.1021/acsmedchemlett.5b00495

Cited by 54 publications

(42 citation statements)

References 35 publications

(56 reference statements)

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“…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].…”

Section: Discussionsupporting

confidence: 86%

“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent. Biological activity assays identify the thiazolethioacetamides can inhibit ImiS with IC50 values of 0.17 to 0.70 μM. For two of them, the IC50 values against VIM-2 were 2.2 and 19.2 μM, which is lower than in our previous report. Eight of the thiazolethioacetamides are able to restore antibacterial activity of cefazolin against E.coli-ImiS by 2–4 fold. An analysis of the structure–activity relation and molecule docking show that the style and position of electron withdrawing groups in aromatic substituents play a crucial role in the inhibitory activity of thiazolethioacetamides. These results indicate that thiazolethioacetamides can serve as a potential skeleton of MβL inhibitors.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

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

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“…In a follow‐up study, the team reported a new series of NDM‐1 inhibitors based on triazolylthioacetamide scaffolds. These compounds all showed specific inhibitory activity against NDM‐1 with IC 50 values ranging from 0.15 to 1.90 μM (Xiang et al., ; Zhai et al., ). At the same time, the inhibitory effect of the azolylthioacetamide compound on VIM‐2 was also discovered.…”

Section: Progress In Designing Metallo‐β‐lactamase Inhibitorsmentioning

confidence: 99%

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

et al. 2019

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After more than 80 years of development, β‐lactam drugs have become the most widely used high‐efficiency, low‐toxic broad‐spectrum antibacterial drugs. However, with the widespread use and even abuse of those drugs, the resistance of major pathogens to β‐lactam drugs has increased over years, which has become a thorny problem to the public health. A common mechanism of the resistance to β‐lactams is the producing of β‐lactamases, which can hydrolyze the β‐lactam ring and inactivate these drugs. Metallo‐β‐lactamases (MBLs) are one kind of β‐lactamases that require metal ions for their catalytic activities. Although it is a well‐known strategy to recover the efficacy of β‐lactams by the combination of β‐lactamase inhibitors, there are still no MBL inhibitors that can be used in clinical practice. Therefore, it is urgent to develop MBL inhibitors. This review outlines the currently discovered MBL inhibitors with an emphasis on various strategies and approaches taken to discover MBL inhibitors, which may lead to diverse classes of inhibitors. Recent progress, particularly new screening methods, and the rational design of potent MBL inhibitors are discussed.

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“…Recently, we found that azolylthioacetamides are the potent MβL inhibitors [23][24][25][26], these compounds showed broad-spectrum inhibition on CcrA [24], NDM-1 [23,24,26], ImiS [24][25][26], and L1 [24], as the representative of three subclasses enzymes, respectively. Further, we reported an aromatic carboxyl substituted azolylthioacetamide as an inhibitor of VIM-2, which provided the binding via the complex crystal structure of enzyme and inhibitor [27].…”

Section: Introductionmentioning

confidence: 99%

Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-β-Lactamase 2 (VIM-2) Inhibitor

Yang

Zhang

et al. 2020

Biomolecules

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Inhibition of β-lactamases presents a promising strategy to restore the β-lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides 1a–j inhibited VIM-2, exhibiting an IC50 value in the range of 20.6–58.6 μM. The structure-activity relationship study revealed that replacing the aliphatic carboxylic acid with aromatic carboxyl improved the inhibitory activity of 2-triazolylthioacetamides against VIM-2. 1a–j (16 mg/mL) restored the antibacterial activity of cefazolin against E. coli cell expressing VIM-2, resulting in a 4–8-fold reduction in MICs. The isothermal titration calorimetry (ITC) characterization suggested that the primary binding 2-triazolylthioacetamide (1b, 1c, or 1h) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with 1b was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that 1b bound to two Zn(II) ions of the enzyme active sites, formed H-bound with Asn233 and structure water molecule, and interacted with the hydrophobic pocket of enzyme activity center utilizing hydrophobic moieties; especially for the phenyl of aromatic carboxyl which formed π-π stacking with active residue His263. These studies confirmed that aromatic carboxyl substituted 2-triazolylthioacetamides are the potent VIM-2 inhibitors scaffold and provided help to further optimize 2-triazolylthioacetamides as VIM-2 even or broad-spectrum MβLs inhibitors.

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Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

Cited by 54 publications

References 35 publications

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

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

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-β-Lactamase 2 (VIM-2) Inhibitor

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