Azolylthioacetamide: A Highly Promising Scaffold for the Development of Metallo-β-lactamase Inhibitors

Yang, Shao-Kang; Kang, Joon S.; Oelschlaeger, Peter; Yang, Ke‐Wu

doi:10.1021/ml500534c

Cited by 47 publications

(48 citation statements)

References 35 publications

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“…A few triazole–thione analogues with no amino group at the 4‐position were reported to be modest inhibitors of the IMP‐1 MBL or were shown to be inactive against the CcrA, ImiS, and L1 MBLs at 50 μ m . Other triazole–thione compounds with an alkylated sulfur atom have also been published more recently, and the structure of the complex formed by one of these compounds with VIM‐2 showed that the two zinc atoms were coordinated by the nitrogen atoms at the 1‐ and 2‐positions of the heterocycle …”

Section: Introductionmentioning

confidence: 99%

1,2,4‐Triazole‐3‐thione Compounds as Inhibitors of Dizinc Metallo‐β‐lactamases

et al. 2017

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Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC values toward plasmodial glyoxalase II were in the 10 μm range.

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Section: Introductionmentioning

confidence: 99%

1,2,4‐Triazole‐3‐thione Compounds as Inhibitors of Dizinc Metallo‐β‐lactamases

et al. 2017

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“…In this work, we synthesized a series of 2-triazolylthioacetamides as previously reported [25], tested their inhibitory activity against VIM-2, and evaluated their efficiency to restore antibacterial activity of cefazolin against bacteria expressing VIM-2. Further, the binding affinities of 2triazolylthioacetamides to VIM-2 were determined by isothermal titration calorimetry (ITC).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, several complexes of crystal structures of VIM-2 with small molecules have been reported [7,11,13].Recently, we found that azolylthioacetamides are the potent MβL inhibitors [23-26], these compounds showed broad-spectrum inhibition on CcrA [24], 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].In this work, we synthesized a series of 2-triazolylthioacetamides as previously reported [25], tested their inhibitory activity against VIM-2, and evaluated their efficiency to restore antibacterial activity of cefazolin against bacteria expressing VIM-2.Further, the binding affinities of 2-triazolylthioacetamides to VIM-2 were determined by isothermal titration calorimetry (ITC). Finally, the crystal structure of VIM-2 in complex with a 2-triazolylthioacetamide molecule was determined and the interaction between enzyme and inhibitor was explored by crystallographic studies.…”

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confidence: 99%

“…Recently, we found that azolylthioacetamides are the potent MβL inhibitors [23-26], these compounds showed broad-spectrum inhibition on CcrA [24], 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].…”

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confidence: 99%

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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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“…Interestingly, several recent reports have described new strategies and scaffolds to advance of field of MBL inhibitor discovery. These include: (i) the design of mechanism-based inhibitors where the anionic azanide intermediate is well-stabilized, thus leading to prolonged residence times in the active sites of MBLs[36]; (ii) zinc-binding azolylthioacetamides which have been found to serve as (sub)micromolar inhibitors of CcrA, NDM-1, ImiS and L1[79,80]; (iii) natural product zinc chelators such as aspergillomarasmine A…”

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confidence: 99%