Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 μg·mL-1 (5 μM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 μg·mL-1. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-β-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding.

• Klíčová slova
• DprE1, RpsA, anilides, antimycobacterial activity, cytotoxicity, pyrazinamide, pyrazinoic acid,
• MeSH
• alkoholoxidoreduktasy antagonisté a inhibitory   chemie   MeSH
• antibakteriální látky chemie   farmakologie   MeSH
• antifungální látky chemie   farmakologie   MeSH
• bakteriální proteiny antagonisté a inhibitory   chemie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti metody   MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• počítačová simulace MeSH
• pyraziny chemie   farmakologie   MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu metody   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkoholoxidoreduktasy MeSH
• antibakteriální látky MeSH
• antifungální látky MeSH
• bakteriální proteiny MeSH
• DprE1 protein, Mycobacterium tuberculosis MeSH Prohlížeč
• pyraziny MeSH

Aminodehalogenation of 3-chloropyrazine-2-carboxamide with variously substituted benzylamines yielded a series of fifteen 3-benzylaminopyrazine-2-carboxamides. Four compounds possessed in vitro whole cell activity against Mycobacterium tuberculosis H37Rv that was at least equivalent to that of the standard pyrazinamide. MIC values ranged from 6 to 42 μM. The best MIC (6 μM) was displayed by 3-[(4-methylbenzyl)amino]pyrazine-2-carboxamide (8) that also showed low cytotoxicity in the HepG2 cell line (IC50 ≥ 250 μM). Only moderate activity against Enterococcus faecalis and Staphylococcus aureus was observed. No activity was detected against any of tested fungal strains. Molecular docking with mycobacterial enoyl-ACP reductase (InhA) was performed to investigate the possible target of the prepared compounds. Active compounds shared common binding interactions of known InhAinhibitors. Antimycobacterial activity of the title compounds was compared to the previously published benzylamino-substituted pyrazines with differing substitution on the pyrazine core (carbonitrile moiety). The title series possessed comparable activity and lower cytotoxicity than molecules containing a carbonitrile group on the pyrazine ring.

• Klíčová slova
• antibacterials, antifungals, benzylamines, cytotoxicity, microwave-assisted, pyrazinamide, tuberculosis,
• MeSH
• amidy chemie   MeSH
• antibakteriální látky chemická syntéza   farmakologie   MeSH
• antifungální látky chemická syntéza   farmakologie   MeSH
• antiinfekční látky chemická syntéza   farmakologie   MeSH
• antituberkulotika chemická syntéza   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• pyrazinamid chemická syntéza   farmakologie   MeSH
• pyraziny chemie   MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amidy MeSH
• antibakteriální látky MeSH
• antifungální látky MeSH
• antiinfekční látky MeSH
• antituberkulotika MeSH
• pyrazinamid MeSH
• pyraziny MeSH