Design, synthesis and biological evaluation of substituted 3-amino-N-(thiazol-2-yl)pyrazine-2-carboxamides as inhibitors of mycobacterial methionine aminopeptidase 1

Juhás, Martin; Pallabothula, Vinod Sukanth Kumar; Grabrijan, Katarina; Šimovičová, Martina; Janďourek, Ondřej; Konečná, Klára; Bárta, Pavel; Paterová, Pavla; Gobec, Stanislav; Zítko, Jan

doi:10.1016/j.bioorg.2021.105489

Cited by 7 publications

(6 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the final coupling, we have investigated several procedures, including coupling reagents such as 1,1′-carbonyldiimidazole (CDI). As before [ 24 ], CDI coupling was successful for the derivatives containing the 2-AMT but failed in all syntheses involving 2-AMO and was thus discontinued in favor of acylation by acyl chlorides. In general, we observed low to moderate final yields for the majority of compounds.…”

Section: Resultsmentioning

confidence: 74%

“…Three compounds presented in this study ( 1a , 2a , 3a ―all belonging to subtype I) and similar compounds bearing a thiazole ring have been previously evaluated for inhibitory activity against methionine aminopeptidase (MetAP), a known target for both antimicrobial and anticancer agents [ 24 , 50 ]. In the current research, we were mainly focused on antimicrobial activity, and our in vitro cytotoxicity screening in the HepG2 cancer cell line showed that the three mentioned compounds are non-cytotoxic (IC 50 > 1000 µM) and hence could be discarded as potential anticancer agents.…”

Section: Resultsmentioning

confidence: 99%

“…Antimicrobial activity and cytotoxicity screenings were performed as published previously [ 24 , 56 ]. The full description of the used methodology is available in the Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

et al. 2022

Self Cite

View full text Add to dashboard Cite

Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted N-oxazolyl- and N-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially Mycobacterium tuberculosis (best MICH37Ra = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k’w and water solubility (log S) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial β-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations.

show abstract

Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…For antibacterial and antifungal evaluation, microplate broth dilution was performed according to the slightly modified methodology of The European Committee on Antimicrobial Susceptibility Testing (EUCAST) in correspondence with our earlier publication [ 16 ]. Various strains of pathogenic bacterial strains and fungi were used to determine the inhibitory activity of the prepared compounds.…”

Section: Resultsmentioning

confidence: 99%

Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity

et al. 2022

Self Cite

View full text Add to dashboard Cite

Multidrug-resistant tuberculosis (MDR-TB) poses a significant threat to mankind and as such earned its place on the WHO list of priority pathogens. New antimycobacterials with a mechanism of action different to currently used agents are highly required. This study presents the design, synthesis, and biological evaluation of 3-acylaminopyrazine-2-carboxamides derived from a previously reported inhibitor of human prolyl-tRNA synthetase. Compounds were evaluated in vitro against various strains of mycobacteria, pathogenic bacteria, and fungi of clinical significance. In general, high activity against mycobacteria was noted, while the antibacterial and antifungal activity was minimal. The most active compounds were 4’-substituted 3-(benzamido)pyrazine-2-carboxamides, exerting MIC (Minimum Inhibitory Concentration) from 1.95 to 31.25 µg/mL. Detailed structure–activity relationships were established and rationalized in silico with regard to mycobacterial ProRS as a probable target. The active compounds preserved their activity even against multidrug-resistant strains of Mycobacterium tuberculosis. At the same time, they were non-cytotoxic against HepG2 human hepatocellular carcinoma cells. This project is the first step in the successful repurposing of inhibitors of human ProRS to inhibitors of mycobacterial ProRS with antimycobacterial activity.

show abstract

“…The evaluation results are given in Table 19. Juhas et al [26] developed a series of 3-substituted N-(thiazol-2-yl)pyrazine-2-carboxamides analogs using Scheme 19. In the initial step, 3-aminopyrazine-2-carboxylic acid was refluxed with a mixture of aminothiazole and anhydrous DMSO at 70 C for 1 h to form intermediate compound 73.…”

Section: S C H Ementioning

confidence: 99%

Synthesis and antimycobacterial evaluation of pyrazinamide, benzimidazole and carboxamide derivatives

Shah

Kumar

et al. 2022

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

Due to the unusual structure and chemical composition of the mycobacterial cell wall, it is difficult to develop effective antitubercular treatment as it leads to many antibiotics not working and preventing drug entry. It also leads to the problem of more drug resistance. Tuberculosis (TB) is still the second most contagious disease with about 33% of the world's population being affected mainly by drug-resistant TB (MDR, XDR), chronic infections, and the combination of TB and human immunodeficiency virus (HIV). Therefore, there is an urgent need for the development of novel antitubercular drugs that will shorten the total duration of effective treatment taken under directly observed treatment, short-course (DOTS) guidance, solve the problem of multiple drug resistance, and provide effective treatment for TB diseases. In this review, we considered various synthetic schemes of pyrazinamide, benzimidazole, and carboxamide derivatives that have antitubercular properties that can overcome the resistance to parental drugs and thus act as an effective alternative.

show abstract

Design, synthesis and biological evaluation of substituted 3-amino-N-(thiazol-2-yl)pyrazine-2-carboxamides as inhibitors of mycobacterial methionine aminopeptidase 1

Cited by 7 publications

References 47 publications

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity

Synthesis and antimycobacterial evaluation of pyrazinamide, benzimidazole and carboxamide derivatives

Contact Info

Product

Resources

About