Identification of <i>Mycobacterium tuberculosis</i> leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one

Gudzera, O. I.; Golub, Andriy G.; Bdzhola, Volodymyr G.; Volynets, Galyna P.; Kovalenko, Oksana; Boyarshin, Konstantin; Yaremchuk, A.; Protopopov, M. V.; Yarmoluk, S. M.; Tukalo, M. A.

doi:10.1080/14756366.2016.1190712

Cited by 20 publications

(10 citation statements)

References 12 publications

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“…Initially, in clinical trials, there was rapid resistance issues with this compound when administrated alone, however it is now being tested in combination therapies with some success [25]. Research using receptor-based virtual screening methods, conducted at the National Academy of Science of Ukraine in conjunction with Otava Chemicals, identified derivatives of two compound series, 5-phenylamino-2H- [1,2,4]triazin-3-one and N-Benzylidene-N'-thiazol-2-ylhydrazine [26]. These compounds have shown promising pre-clinical activity against Mycobacterium tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Chemical Compounds that Inhibit Leucyl-tRNA Synthetase from Pseudomonas aeruginosa

Zamacona

Medellin

et al. 2020

CDDT

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Background: Pseudomonas aeruginosa is an opportunistic multi-drug resistance pathogen implicated as the causative agent in a high-percentage of nosocomial and community acquired bacterial infections. The gene encoding leucyl-tRNA synthetase (LeuRS) from P. aeruginosa was overexpressed in Escherichia coli and the resulting protein was characterized. Methods: LeuRS was kinetically evaluated and the KM values for interactions with leucine, ATP and tRNA were 6.5, 330, and 3.0 μM, respectively. LeuRS was developed into a screening platform using scintillation proximity assay (SPA) technology and used to screen over 2000 synthetic and natural chemical compounds. Results: The initial screen resulted in the identification of two inhibitory compounds, BT03C09 and BT03E07. IC50s against LeuRS observed for BT03C09 and BT03E07 were 23 and 15 μM, respectively. The minimum inhibitory concentrations (MIC) were determined against nine clinically relevant bacterial strains. In time-kill kinetic analysis, BT03C09 was observed to inhibit bacterial growth in a bacteriostatic manner, while BT03E07 acted as a bactericidal agent. Neither compound competed with leucine or ATP for binding LeuRS. Limited inhibition was observed in aminoacylation assays with the human mitochondrial form of LeuRS, however when tested in cultures of human cell line, BT03C09 was toxic at all concentration whereas BT03E07 only showed toxic effects at elevated concentrations. Conclusion: Two compounds were identified as inhibitors of LeuRS in a screen of over 2000 natural and synthetic compounds. After characterization one compound (BT03E07) exhibited broad spectrum antibacterial activity while maintaining low toxicity against human mitochondrial LeuRS as well as against human cell cultures.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Chemical Compounds that Inhibit Leucyl-tRNA Synthetase from Pseudomonas aeruginosa

Zamacona

Medellin

et al. 2020

CDDT

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“…Moreover, compared with compound 28, their LeuRS residual activity decreased significantly. 87 These compounds were found to inhibit the LeuRS mainly by interacting with the amino acid residues such as Gly108, Leu111, Gly715, Tyr 716 and forming a hydrogen bond with Gln714 in the leucyl-binding region.…”

Section: Inhibitors Targeting the Editing Site Of Leursmentioning

confidence: 99%

Recent development of leucyl-tRNA synthetase inhibitors as antimicrobial agents

Zhang

2019

Med. Chem. Commun.

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“…This compound is a derivative of N‐Benzylidene‐N'‐thiazol‐2‐yl‐hydrazine (Gudzera et al, 2016), the 4‐thiazolidinon core of this compound has been found to display anti‐tubercular activity (Gudzera et al, 2016). Gudzera et al (2016) also screened 63 analogues of 4‐{[4‐(4‐Bromo‐phenyl)‐thiazol‐2‐yl]hydrazonomethyl}‐2‐methoxy‐6‐nitro‐phenol for inhibitory activity against M. tuberculosis Leu‐RS. Two of these compounds, presented in Figure 6, are 5‐(5‐Chloro‐2‐hydroxy‐phenylamino)‐6‐methyl‐2H‐[1,2,4]triazin‐3‐one and 5‐(5‐Chloro‐2‐hydroxy‐phenylamino)‐2H‐[1,2,4]‐triazin‐3‐one which inhibited M. tuberculosis Leu‐RS with an IC 50 = 7.6 μM and 7.2 μM, respectively (Gudzera et al, 2016).…”

Section: Screening Of Drug‐like Libraries Against Tubercular Aminoacyl‐trna Synthasesmentioning

confidence: 99%

“…Gudzera et al (2016) also screened 63 analogues of 4‐{[4‐(4‐Bromo‐phenyl)‐thiazol‐2‐yl]hydrazonomethyl}‐2‐methoxy‐6‐nitro‐phenol for inhibitory activity against M. tuberculosis Leu‐RS. Two of these compounds, presented in Figure 6, are 5‐(5‐Chloro‐2‐hydroxy‐phenylamino)‐6‐methyl‐2H‐[1,2,4]triazin‐3‐one and 5‐(5‐Chloro‐2‐hydroxy‐phenylamino)‐2H‐[1,2,4]‐triazin‐3‐one which inhibited M. tuberculosis Leu‐RS with an IC 50 = 7.6 μM and 7.2 μM, respectively (Gudzera et al, 2016). These compounds demonstrated 10‐fold lower inhibitory activity towards H. sapiens cytoplasmic Leu‐RS with an IC 50 = 68.9 μM and 76.5 μM, respectively (Gudzera et al, 2016).…”

Section: Screening Of Drug‐like Libraries Against Tubercular Aminoacyl‐trna Synthasesmentioning

confidence: 99%

A consequence of drug targeting of aminoacyl‐tRNA synthetases in Mycobacteriumtuberculosis

2021

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Drug‐resistant Mycobacterium tuberculosis poses a great threat to public health and remains one of the red‐flag tagged infectious diseases, with the tendency of comorbidity with other disease conditions such as HIV/AIDS. This perhaps is responsible for redoubling of effort in tuberculosis research and continuous change in patient management to optimize the drug therapy. Aminoacyl‐tRNA synthetases are essential enzymes in M. tuberculosis that catalyse the transfer of a particular amino acid to its corresponding specific tRNA to form an aminoacyl‐tRNA. These enzymes are believed to be novel antibacterial, antifungal and antiparasitic drug targets because of their role in the process of protein translation. Therefore, their existence as a compliment of M. tuberculosis has attracted a lot of research interest with the aim of curbing the scourge and provide the most effective drug in the treatment of tuberculosis. This leads to the discovery of a pool of aminoacyl‐tRNA synthetases with their essential inhibitors. This review seeks to articulate the current advances in the development of new TB drugs exhibiting novelty in their mode of action with specific emphasis on aminoacyl‐tRNA synthetases as drug targets.

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Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one

Cited by 20 publications

References 12 publications

Identification and Characterization of Chemical Compounds that Inhibit Leucyl-tRNA Synthetase from Pseudomonas aeruginosa

Identification and Characterization of Chemical Compounds that Inhibit Leucyl-tRNA Synthetase from Pseudomonas aeruginosa

Recent development of leucyl-tRNA synthetase inhibitors as antimicrobial agents

A consequence of drug targeting of aminoacyl‐tRNA synthetases in Mycobacteriumtuberculosis

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