Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656)

Li, Xianfeng; Hernandez, Vincent; Rock, Fernando; Choi, Wai; Mak, Yvonne S.L.; Mohan, Manisha; Mao, Wenzhe; Zhou, Yasheen; Easom, Eric E.; Plattner, Jacob J.; Zou, Wenli; Pérez-Herrán, Esther; Giordano, Ilaria; Mendoza-Losana, Alfonso; Alemparte, Carlos; Rullás, Joaquín; Angulo-Barturen, Íñigo; Crouch, Sabrinia; Ortega, Fátima; Barros, David; Alley, M.R.K.

doi:10.1021/acs.jmedchem.7b00631

Cited by 138 publications

(108 citation statements)

References 27 publications

(52 reference statements)

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“…Besides their antiparasitic effects, ARS inhibitors also played an important role in the antibacterial and antifungal processes [45][46][47][48] . By evaluating the inhibitory effect of a series of 3-aminomethyl 4-halogen benzoxaboroles on Mtb leucyl-tRNA synthetase (LeuRS), Li et al 49 found that one of the compounds, GSK656, was highly selective for Mtb LeuRS and had good antitubercular activity and tolerability in the mid-nanomolar range. Moreover, thiazolin-4-one derivatives as WRS inhibitors showed higher activity against Gram positive bacterial strains than Gram negative bacterial strains 50 .…”

Section: Pathogen Arss Serve As Anti-infective Targetsmentioning

confidence: 99%

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

Nie

Sun

et al. 2019

Cell Death Dis

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Aminoacyl-tRNA synthetases (ARSs) play a vital role in protein synthesis by linking amino acids to their cognate transfer RNAs (tRNAs). This typical function has been well recognized over the past few decades. However, accumulating evidence reveals that ARSs are involved in a wide range of physiological and pathological processes apart from translation. Strikingly, certain ARSs are closely related to different types of immune responses. In this review, we address the infection and immune responses induced by pathogen ARSs, as well as the potential anti-infective compounds that target pathogen ARSs. Meanwhile, we describe the functional mechanisms of ARSs in the development of immune cells. In addition, we focus on the roles of ARSs in certain immune diseases, such as autoimmune diseases, infectious diseases, and tumor immunity. Although our knowledge of ARSs in the immunological context is still in its infancy, research in this field may provide new ideas for the treatment of immune-related diseases.

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Section: Pathogen Arss Serve As Anti-infective Targetsmentioning

confidence: 99%

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

Nie

Sun

et al. 2019

Cell Death Dis

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“…The aminoacylation assay was performed according to the literature [32,33]. All test compounds were dissolved in CH 3 OH.…”

Section: Aminoacylation Assaymentioning

confidence: 99%

Synthesis, Characterization, and Biological Evaluation of Novel 7-Oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic Acid Derivatives

Cai

Xie

et al. 2020

Molecules

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A series of novel 7-oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic acid derivatives was synthesized in good yields by a multi-step procedure that included the generation of the S-alkylated derivatives from 6-substituted arylmethyl-3-mercapto-1,2,4-triazin-5-ones with ethyl 2-chloroacetoacetate, intramolecular cyclization with microwave irradiation, hydrolysis and amidation. All of the target compounds were fully characterized through 1H-NMR, 13C-NMR and HRMS spectra. The intramolecular cyclization occurred regioselectively at the N2-position of 1,2,4-triazine ring, which was confirmed by compound 3e using single-crystal X-ray diffraction analysis. The antibacterial and antitubercular activities of the target compounds were evaluated. Compared with Ciprofloxacin and Rifampicin, compounds 5d, 5f and 5g containing the terminal amide fragment exhibited broad spectrum antibacterial activity, and carboxylic acid derivatives or its corresponding ethyl esters had less effect on antibacterial properties. The most potent compound 5f also displayed excellent in vitro antitubercular activity against Mycobacterium smegmatis (minimum inhibitory concentration (MIC) = 50 μg/mL) and better growth inhibition activity of leucyl-tRNA synthetase (78.24 ± 4.05% at 15 μg/mL).

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“…18,19 While, there are no commercially approved tRNA synthase inhibitors for the treatment of TB, several inhibitors have been outlined in the literature. [20][21][22][23] Specifically, the 3-aminomethyl compounds containing boron that successfully inhibit mycobacterial leucyl-tRNA synthetase, 21,22 as well as, various inhibitors of aspartyl-tRNA synthetase. 20,23 Drug discovery and target identification is a laborious process that is bottlenecked at several key points.…”

Section: Introductionmentioning

confidence: 99%

Development of a novel secondary phenotypic screen to identify hits within the mycobacterial protein synthesis pipeline

et al. 2020

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Background: Whole-cell phenotypic screening is the driving force behind modern anti-tubercular drug discovery efforts. Focus has shifted from screening for bactericidal scaffolds to screens incorporating target deconvolution. Target-based screening aims to direct drug discovery toward known effective targets and avoid investing resources into unproductive lines of enquiry. The protein synthesis pipeline, including RNA polymerase and the ribosome, is a clinically proven target in Mycobacterium tuberculosis. Screening for new hits of this effective target pathway is an invaluable tool in the drug discovery arsenal. Methods: Using M. tuberculosis H37Rv augmented with anhydrotetracycline-inducible expression of mCherry, a phenotypic screen was developed for the identification of protein synthesis inhibitors in a medium throughput screening format. Results: The assay was validated using known inhibitors of protein synthesis to show a dose-dependent reduction in mCherry fluorescence. This was expanded to a proprietary screen of hypothetical protein synthesis hits and modified to include quantitative viability measurement of cells using resazurin. Conclusion: Following the success of the proprietary screen, a larger scale screen of the GlaxoSmithKline anti-tubercular library containing 2799 compounds was conducted. Combined single shot and dose-response screening yielded 18 hits, 0.64% of all screened compounds.

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Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656)

Cited by 138 publications

References 27 publications

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

Synthesis, Characterization, and Biological Evaluation of Novel 7-Oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic Acid Derivatives

Development of a novel secondary phenotypic screen to identify hits within the mycobacterial protein synthesis pipeline

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