pyrazine
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Pyrazine derivatives show a wide range of biological activities. 1-Pyrazin-2-ylethan-1-ones have served as food flavourants, and together with pyrazine-2-carbonitriles have been widely used as intermediates in the synthesis of various heterocyclic compounds. In our laboratory, substituted pyrazine-2-carbonitriles and 1-pyrazin-2-ylethan-1-ones have been used as intermediates for the preparation of potential antifungal and antimycobacterial drugs. Using established methods, a library of pyrazine derivatives was synthesized. Homolytic alkylation of commercially available pyrazine-2-carbonitrile yielded a series of 5-alkylpyrazine-2-carbonitriles which were converted into the corresponding 1-(5-alkylpyrazin-2-yl)ethan-1-ones (5-alkyl-2-acetylpyrazines) via the Grignard reaction. Homolytic acetylation of pyrazine-2-carbonitrile yielded 5-acetylpyrazine-2-carbonitrile. Using the same procedure, 3-acetyl-5-tert-butylpyrazine-2-carbonitrile was obtained with 5-tert-butylpyrazine-2-carbonitrile as a starting material. The hydrophobicity of the compounds was determined both experimentally (RP-HPLC) and by computation (CS ChemOffice Ultra version 9.0, ACD/LogP version 1.0 and ACD/LogP version 9.04), and both the approaches were compared. New hydrophobicity constants ? based on experimental results were derived. These constants are markedly different from tabulated constants ? valid for benzene rings, and can be widely used in estimating physicochemical properties of new biologically active pyrazines.
The development of new antimicrobial agents for the treatment of infectious diseases remains challenging due to the increasing impact of antibiotic resistance. Since salicylanilides and esters of pyrazine-2-carboxylic acid have been described as potential antimicrobials, we have designed and synthesized a series of 2-(phenylcarbamoyl)phenyl pyrazine-2-carboxylates. These were evaluated in vitro for the activity against fungi and Gram-positive and Gram-negative bacteria. All derivatives showed significant antibacterial activity against Gram-positive strains (MIC ≥ 0.98 μmol/L) including methicillin-resistant Staphylococcus aureus. The most active molecule was 5-chloro-2-(3-chlorophenylcarbamoyl)phenyl pyrazine-2-carboxylate. With one exception these esters were at least partly active against fungi tested strains, in particular against mould strains (MIC ≥ 1.95 μmol/L). The most active antifungal agent overall proved to be 2-(4-bromophenylcarbamoyl)-4-chlorophenyl pyrazine-2-carboxylate.
- MeSH
- antibakteriální látky chemie farmakologie MeSH
- antifungální látky chemie farmakologie MeSH
- gramnegativní bakterie účinky léků MeSH
- houby účinky léků MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- pyraziny chemie farmakologie MeSH
- salicylanilidy chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3-chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by analytical methods and tested for antimicrobial and antiviral activity. The antimycobacterial MIC values against Mycobacterium tuberculosis H37Rv of the most effective compounds, 3-(hexylamino)-, 3-(heptylamino)- and 3-(octylamino)-N-methyl-pyrazine-2-carboxamides 14‒16, was 25 μg/mL. The compounds inhibited photosystem 2 photosynthetic electron transport (PET) in spinach chloroplasts. This activity was strongly connected with the lipophilicity of the compounds. For effective PET inhibition longer alkyl chains in the 3-(alkylamino) substituent in the N-alkyl-3-(alkylamino)pyrazine-2-carboxamide molecule were more favourable than two shorter alkyl chains.
- MeSH
- antituberkulotika chemická syntéza farmakologie MeSH
- bakteriální proteiny antagonisté a inhibitory metabolismus MeSH
- chloroplasty metabolismus MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis účinky léků metabolismus MeSH
- pyrazinamid chemická syntéza chemie farmakologie MeSH
- pyraziny chemická syntéza farmakologie MeSH
- Spinacia oleracea metabolismus MeSH
- syntázy mastných kyselin antagonisté a inhibitory metabolismus MeSH
- transport elektronů účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Infectious diseases, such as tuberculosis and invasive mycoses, represent serious health problems. As a part of our long-term efforts to find new agents for the treatment of these diseases, a new series of pyrazine analogs of chalcones bearing an isopropyl group in position 5 of the pyrazine ring was prepared. The structures of the compounds were corroborated by IR and NMR spectroscopy and their purity confirmed by elemental analysis. The susceptibility of eight fungal strains to the studied compounds was tested. The results have been compared with the activity of some previously reported propyl derivatives. The only strain that was susceptible to the studied compounds was Trichophyton mentagrophytes. It was found that replacing a non-branched propyl with a branched isopropyl did not have a decisive and unequivocal influence on the in vitro antifungal activity against T. mentagrophytes. In vitro activity against Trichophyton mentagrophytes comparable with that of fluconazole was exhibited by nitro-substituted derivatives. Unfortunately, no compound exhibited efficacy comparable with that of terbinafine, which is the most widely used agent for treating mycoses caused by dermatophytes. Some of the prepared compounds were assayed for antimycobacterial activity against M. tuberculosis H37Rv. The highest potency was also displayed by nitro-substituted compounds. The results of the present study are in a good agreement with our previous findings and confirm the positive influence of electron-withdrawing groups on the B-ring of chalcones on the antifungal and antimycobacterial activity of these compounds.
- MeSH
- antifungální látky chemická syntéza chemie farmakologie MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- Cercopithecus aethiops MeSH
- chalkonoidy chemická syntéza chemie farmakologie MeSH
- houby klasifikace účinky léků MeSH
- magnetická rezonanční spektroskopie s uhlíkem 13C MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- pyraziny chemie MeSH
- spektrofotometrie infračervená MeSH
- Vero buňky MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
