A hit expansion of 3-benzamidopyrazine-2-carboxamide: Toward inhibitors of prolyl-tRNA synthetase with antimycobacterial activity
Language English Country Germany Media print-electronic
Document type Journal Article
Grant support
NU21-05-00482 (grant to J. Z.)
Supported by Ministry of Health of the Czech Republic
The publication was supported by the research project 2200/04/2024-2026 as part of the "Competition for 2024-2026 Postdoctoral Job Positions at the University of Hradec Králové", at the Faculty of Science, University of Hradec Králové (grant to M. J.)
Grant Agency of Charles University with Project GA UK No. 349 721 and Charles University with project SVV 260 666
- Keywords
- 3‐aminopyrazinamide, antimycobacterial, hit expansion, multidrug‐resistant, prolyl‐tRNA synthetase,
- MeSH
- Amino Acyl-tRNA Synthetases antagonists & inhibitors metabolism MeSH
- Antitubercular Agents * pharmacology chemistry chemical synthesis MeSH
- Enzyme Inhibitors pharmacology chemistry chemical synthesis MeSH
- Microbial Sensitivity Tests * MeSH
- Molecular Structure MeSH
- Mycobacterium tuberculosis * drug effects enzymology MeSH
- Pyrazines pharmacology chemistry chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Amino Acyl-tRNA Synthetases MeSH
- Antitubercular Agents * MeSH
- Enzyme Inhibitors MeSH
- prolyl T RNA synthetase MeSH Browser
- Pyrazines MeSH
This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring. This series brought two new compounds (21: R = 2-F, 4-Cl and 22: R = 2-F, 4-Br) with in vitro activity against Mycobacterium tuberculosis H37Rv as well as multidrug-resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25 μg/mL. The lactone-type derivatives 4H-pyrazino[2,3-d][1,3]oxazin-4-ones (Series-3) were inactive, but solvent stability studies of compound 29 indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).
Biomedical Research Centre University Hospital Hradec Králové Hradec Králové Czech Republic
Department of Chemistry University of Milan Milan Italy
Department of Clinical Microbiology University Hospital Hradec Králové Hradec Králové Czech Republic
Department of Pharmaceutical Sciences University of Milan Milan Italy
Faculty of Pharmacy in Hradec Králové Charles University Hradec Králové Czech Republic
Faculty of Science University of Hradec Králové Hradec Králové Czech Republic
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