Synthesis and evaluation of new tyrosyl-tRNA synthetase inhibitors as antibacterial agents based on a N2-(arylacetyl)glycinanilide scaffold

Xiao, Zhu‐Ping; Wei, Wei; Wang, Pengfei; Shi, Wei-Kang; Zhu, Na; Xie, Me-Qun; Sun, Yan; Li, Lingxia; Xie, Yong-Xiang; Zhu, Liang-Song; Tang, Nian; Ouyang, Hongwei; Li, Xianhui; Wang, Guang-cheng; Zhu, Hai‐Liang

doi:10.1016/j.ejmech.2015.08.025

Cited by 11 publications

(6 citation statements)

References 24 publications

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“…For this reason, the Srt A protein attracted the attention of the researchers as an interesting target for the development of antimicrobial and antibiofilm drugs [ 33 ]. Another interesting target is represented by aminoacyl–tRNA synthases (aaRSs) [ 34 ] playing a key role in the translation of nucleic acid sequences into a polypeptide sequence [ 35 ]. Indeed, their inhibition is associated with a blockage of bacterial cell growth due to the interference with protein synthesis [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

“…Another interesting target is represented by aminoacyl–tRNA synthases (aaRSs) [ 34 ] playing a key role in the translation of nucleic acid sequences into a polypeptide sequence [ 35 ]. Indeed, their inhibition is associated with a blockage of bacterial cell growth due to the interference with protein synthesis [ 34 ]. Furthermore, it has to be highlighted that significant differences in the topology of ATP binding domain have been reported between human and bacterial aaRS, probably due to the different functions that these enzymes play in human cells [ 36 ], thus opening the way to the possibility of selectively targeting bacterial aaRSs enzymes [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, their inhibition is associated with a blockage of bacterial cell growth due to the interference with protein synthesis [ 34 ]. Furthermore, it has to be highlighted that significant differences in the topology of ATP binding domain have been reported between human and bacterial aaRS, probably due to the different functions that these enzymes play in human cells [ 36 ], thus opening the way to the possibility of selectively targeting bacterial aaRSs enzymes [ 34 ]. Based on this, a preliminary evaluation of the putative molecular bases of compound 3 antimicrobial and antibiofilm properties was performed by selecting Sortase A (Srt A) protein and aminoacyl–tRNA synthases (aaRSs) as targets in molecular docking analyses.…”

Section: Resultsmentioning

confidence: 99%

“…This makes Srt A a suitable target for the development of novel and effective antibiofilm drugs [ 33 ]. Aminoacyl–tRNA synthases (aaRSs) also represent good candidates as targets of antimicrobial strategies [ 34 ]. Indeed, their inhibition is associated with a blockage of cell growth due to interference with protein synthesis processes [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

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Ephedra foeminea as a Novel Source of Antimicrobial and Anti-Biofilm Compounds to Fight Multidrug Resistance Phenotype

Ismail

Gaglione

Masi

et al. 2023

IJMS

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Plants are considered a wealthy resource of novel natural drugs effective in the treatment of multidrug-resistant infections. Here, a bioguided purification of Ephedra foeminea extracts was performed to identify bioactive compounds. The determination of antimicrobial properties was achieved by broth microdilution assays to evaluate minimal inhibitory concentration (MIC) values and by crystal violet staining and confocal laser scanning microscopy analyses (CLSM) to investigate the antibiofilm capacity of the isolated compounds. Assays were performed on a panel of three gram-positive and three gram-negative bacterial strains. Six compounds were isolated from E. foeminea extracts for the first time. They were identified by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) analyses as the well-known monoterpenoid phenols carvacrol and thymol and as four acylated kaempferol glycosides. Among them, the compound kaempferol-3-O-α-L-(2″,4″-di-E-p-coumaroyl)-rhamnopyranoside was found to be endowed with strong antibacterial properties and significant antibiofilm activity against S. aureus bacterial strains. Moreover, molecular docking studies on this compound suggested that the antibacterial activity of the tested ligand against S. aureus strains might be correlated to the inhibition of Sortase A and/or of tyrosyl tRNA synthase. Collectively, the results achieved open interesting perspectives to kaempferol-3-O-α-L-(2″,4″-di-E-p-coumaroyl)-rhamnopyranoside applicability in different fields, such as biomedical applications and biotechnological purposes such as food preservation and active packaging.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Ephedra foeminea as a Novel Source of Antimicrobial and Anti-Biofilm Compounds to Fight Multidrug Resistance Phenotype

Ismail

Gaglione

Masi

et al. 2023

IJMS

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“…A series of compounds were developed and tested against TyrRS from S. aureus and were observed to have low micromolar IC 50 values and activity against cultures of S. aureus . 20 More recently, adenosine has been attached to the arylfuran scaffold to mimic the Tyr aminoacyl-adenylate. 21 These compounds were also observed to have IC 50 values in the low micromolar range against TyrRS, and moderate antibacterial activity was extended to E. coli and P. aeruginosa .…”

Section: Discussionmentioning

confidence: 99%

Two Forms of Tyrosyl-tRNA Synthetase from Pseudomonas aeruginosa: Characterization and Discovery of Inhibitory Compounds

et al. 2020

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Pseudomonas aeruginosa is a multidrug-resistant (MDR) pathogen and a causative agent of both nosocomial and community-acquired infections. The genes ( tyrS and tyrZ) encoding both forms of P. aeruginosa tyrosyl-tRNA synthetase (TyrRS-S and TyrRS-Z) were cloned and the resulting proteins purified. TyrRS-S and TyrRS-Z were kinetically evaluated and the Km values for interaction with Tyr, ATP, and tRNATyr were 172, 204, and 1.5 μM and 29, 496, and 1.9 μM, respectively. The kcatobs values for interaction with Tyr, ATP, and tRNATyr were calculated to be 3.8, 1.0, and 0.2 s−1 and 3.1, 3.8, and 1.9 s−1, respectively. Using scintillation proximity assay (SPA) technology, a druglike 2000-compound library was screened to identify inhibitors of the enzymes. Four compounds (BCD37H06, BCD38C11, BCD49D09, and BCD54B04) were identified with inhibitory activity against TyrRS-S. BCD38C11 also inhibited TyrRS-Z. The IC50 values for BCD37H06, BCD38C11, BCD49D09, and BCD54B04 against TyrRS-S were 24, 71, 65, and 50 μM, respectively, while the IC50 value for BCD38C11 against TyrRS-Z was 241 μM. Minimum inhibitory concentrations (MICs) were determined against a panel of clinically important pathogens. All four compounds were observed to inhibit the growth of cultures of both Gram-positive and Gram-negative bacteria organisms with a bacteriostatic mode of action. When tested against human cell cultures, none of the compounds were toxic at concentrations up to 400 μg/mL. In mechanism of inhibition studies, BCD38C11 and BCD49D09 selectively inhibited TyrRS activity by competing with ATP for binding. BCD37H06 and BCD54B04 inhibited TyrRS activity by a mechanism other than substrate competition.

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Synthesis, molecular docking studies, and absorption, distribution, metabolism, and excretion prediction of novel sulfonamide derivatives as antibacterial agents

Mohebali

Nazifi

et al. 2019

J Chinese Chemical Soc

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A series of novel sulfonamide-amide derivatives were synthesized from 3-(2,4 dichlorophenylamino)-3-oxopropane-1-sulfonylchloride and a variety of amines under solvent-free conditions at room temperature. 3-(2,4-dichlorophenylamino)-3-oxopropane-1 sulfonylchloride was synthesized in four steps starting from 2,4-dichloroaniline and chloropropanoic acid in good yield and purity. The synthesized compounds were screened for their in vitro antibacterial activity against Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 29213). Molecular docking of sulfonamide derivatives into S. aureus tyrosyl-tRNA synthetase (TyrRS)-active site was also performed and among these, 5m and 5g tightly fit the active sites that might be inhibitors of TyrRS for further investigations. Also in the silico metabolism profile, drug-like properties and absorption, distribution, metabolism, excretion and toxicity (ADMET) of the title compounds were calculated by the preADMET server. K E Y W O R D S

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Synthesis and evaluation of new tyrosyl-tRNA synthetase inhibitors as antibacterial agents based on a N2-(arylacetyl)glycinanilide scaffold

Cited by 11 publications

References 24 publications

Ephedra foeminea as a Novel Source of Antimicrobial and Anti-Biofilm Compounds to Fight Multidrug Resistance Phenotype

Ephedra foeminea as a Novel Source of Antimicrobial and Anti-Biofilm Compounds to Fight Multidrug Resistance Phenotype

Two Forms of Tyrosyl-tRNA Synthetase from Pseudomonas aeruginosa: Characterization and Discovery of Inhibitory Compounds

Synthesis, molecular docking studies, and absorption, distribution, metabolism, and excretion prediction of novel sulfonamide derivatives as antibacterial agents

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