The development of antimicrobial agents represents an up-to-date topic. This study investigated in vitro antimycobacterial activity, mycobacterial isocitrate lyase inhibition and cytotoxicity of salicylanilide pyrazinoates. They may be considered being mutual prodrugs of both antimycobacterial active salicylanilides and pyrazinoic acid (POA), an active metabolite of pyrazinamide, in which these esters are likely hydrolysed without presence of pyrazinamidase/nicotinamidase. Minimum inhibitory concentrations (MICs) of the esters were within the range 0.5-8 μmol/l for Mycobacterium tuberculosis and 1-32 μmol/l for nontuberculous mycobacteria (Mycobacterium avium, Mycobacterium kansasii). All esters showed a weak inhibition (8-17%) of isocitrate lyase at the concentration of 10 μmol/l. The most active pyrazinoates showed MICs for multidrug-resistant tuberculosis strains in the range of 0.125-2 μmol/l and no cross-resistance with clinically used drugs, thus being the most in vitro efficacious salicylanilide esters with 4-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate superiority (MICs⩽0.25 μmol/l). This promising activity is likely due to an additive or synergistic effect of released POA and salicylanilides. Selectivity indexes for the most active salicylanilide pyrazinoates ranged up to 64, making some derivatives being attractive candidates for the next research; 4-bromo-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate showed the most convenient toxicity profile.
- MeSH
- antibakteriální látky farmakologie MeSH
- isocitrátlyasa antagonisté a inhibitory MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná bakteriální léková rezistence MeSH
- Mycobacterium tuberculosis účinky léků genetika MeSH
- netuberkulózní mykobakterie účinky léků růst a vývoj MeSH
- pyrazinamid analogy a deriváty farmakologie MeSH
- salicylanilidy farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of 18 N-alkyl substituted 3-aminopyrazine-2-carboxamides was prepared in this work according to previously experimentally set and proven conditions using microwave assisted synthesis methodology. This approach for the aminodehalogenation reaction was chosen due to higher yields and shorter reaction times compared to organic reactions with conventional heating. Antimycobacterial, antibacterial, antifungal and photosynthetic electron transport (PET) inhibiting in vitro activities of these compounds were investigated. Experiments for the determination of lipophilicity were also performed. Only a small number of substances with alicyclic side chain showed activity against fungi which was the same or higher than standards and the biological efficacy of the compounds increased with rising lipophilicity. Nine pyrazinamide derivatives also inhibited PET in spinach chloroplasts and the IC50 values of these compounds varied in the range from 14.3 to 1590.0 μmol/L. The inhibitory activity was connected not only with the lipophilicity, but also with the presence of secondary amine fragment bounded to the pyrazine ring. Structure-activity relationships are discussed as well.
- MeSH
- antifungální látky chemická syntéza farmakologie MeSH
- antituberkulotika chemická syntéza farmakologie MeSH
- Candida albicans účinky léků MeSH
- chloroplasty účinky léků metabolismus MeSH
- fotosyntéza účinky léků MeSH
- herbicidy chemická syntéza farmakologie MeSH
- hydrofobní a hydrofilní interakce MeSH
- inhibiční koncentrace 50 MeSH
- mikrobiální testy citlivosti MeSH
- mikrovlny MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- pyrazinamid analogy a deriváty chemická syntéza farmakologie MeSH
- Spinacia oleracea účinky léků metabolismus MeSH
- Staphylococcus epidermidis účinky léků MeSH
- transport elektronů účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
5-Chloropyrazinamide (5-Cl-PZA) is an inhibitor of mycobacterial fatty acid synthase I with a broad spectrum of antimycobacterial activity in vitro. Some N-phenylpyrazine-2-carboxamides with different substituents on both the pyrazine and phenyl core possess significant in vitro activity against Mycobacterium tuberculosis. To test the activity of structures combining both the 5-Cl-PZA and anilide motifs a series of thirty 5-chloro-N-phenylpyrazine-2-carboxamides with various substituents R on the phenyl ring were synthesized and screened against M. tuberculosis H37Rv, M. kansasii and two strains of M. avium. Most of the compounds exerted activity against M. tuberculosis H37Rv in the range of MIC = 1.56-6.25 µg/mL and only three derivatives were inactive. The phenyl part of the molecule tolerated many different substituents while maintaining the activity. In vitro cytotoxicity was decreased in compounds with hydroxyl substituents, preferably combined with other hydrophilic substituents. 5-Chloro-N-(5-chloro-2-hydroxyphenyl)pyrazine-2-carboxamide (21) inhibited all of the tested strains (MIC = 1.56 µg/mL for M. tuberculosis; 12.5 µg/mL for other strains). 4-(5-Chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (30) preserved good activity (MIC = 3.13 µg/mL M. tuberculosis) and was rated as non-toxic in two in vitro models (Chinese hamster ovary and renal cell adenocarcinoma cell lines; SI = 47 and 35, respectively).
- MeSH
- antifungální látky chemická syntéza farmakologie MeSH
- antituberkulotika chemická syntéza chemie farmakologie toxicita MeSH
- buněčné linie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- hydrofobní a hydrofilní interakce MeSH
- inhibiční koncentrace 50 MeSH
- křečci praví MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium účinky léků MeSH
- nádorové buněčné linie MeSH
- pyrazinamid analogy a deriváty chemická syntéza chemie farmakologie toxicita MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Design, results of in vitro antimycobacterial evaluation, and study of structure-activity relationships of various pyrazinecarboxylic acid reversible derivatives are presented. This review deals with some pyrazinamide analogues/prodrugs derived from Nphenylpyrazine- 2-carboxamides (1), arylaminopyrazine-2,5-dicarbonitriles (2), aryl/alkylsulphanylpyrazines (3,4), and aroylpyrazines (5) effecting >50% inhibition in the primary antimycobacterial screen. The promising pyrazine candidates for further antimycobacterial evaluation were discovered. Results give good view onto structure-activity relationships of these analogues and promise even better activity of new compounds prepared after some structure optimization experiments.
- MeSH
- antibakteriální látky škodlivé účinky chemie farmakologie MeSH
- buněčné linie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium účinky léků růst a vývoj MeSH
- prekurzory léčiv škodlivé účinky chemie farmakologie MeSH
- pyrazinamid škodlivé účinky analogy a deriváty chemie farmakologie MeSH
- racionální návrh léčiv MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
A series of sixteen pyrazinamide analogues with the -CONH- linker connecting the pyrazine and benzene rings was synthesized by the condensation of chlorides of substituted pyrazinecarboxylic acids with ring-substituted (chlorine) anilines. The prepared compounds were characterized and evaluated for their antimycobacterial and antifungal activity, and for their ability to inhibit photosynthetic electron transport (PET). 6-Chloro-N-(4-chlorophenyl)pyrazine-2-carboxamide manifested the highest activity against Mycobacterium tuberculosis strain H37Rv (65% inhibition at 6.25 μg/mL). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 6-chloro-5-tert-butyl-N-(3,4-dichlorophenyl)pyrazine-2-carboxamide (MIC=62.5 μmol/L). 6-chloro-5-tert-butyl-N-(4-chlorophenyl)pyrazine-2-carboxamide showed the highest PET inhibition in spinach chloroplasts (Spinacia oleracea L.) chloroplasts (IC50=43.0 μmol/L). For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antifungální látky chemická syntéza chemie farmakologie MeSH
- chloroplasty metabolismus MeSH
- chlorované uhlovodíky chemická syntéza chemie farmakologie MeSH
- fotosyntéza účinky léků MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis růst a vývoj MeSH
- pyrazinamid analogy a deriváty chemická syntéza chemie farmakologie MeSH
- Spinacia oleracea metabolismus MeSH
- Trichophyton růst a vývoj MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This paper describes preparation and biological evaluation of pyrazinamide analogues. Pyrazinamide with its simple structure gives a good opportunity for further modification regarding an increase of its antimycobacterial activity. We prepared a series of compounds derived from pyrazine-2,5-dicarbonitrile with arylamino substitution in position 3. All compounds were assayed in vitro against major Mycobacterium and various Fungi species. The best activity was found in 3-{[3-(trifluoromethyl)phenyl]amino}pyrazine-2,5-dicarbonitrile 11 with the value of 6.25 micromol(-1) against M. tuberculosis H(37)Rv and moderate activity against minor Mycobacterium pathogens.
- MeSH
- Absidia účinky léků MeSH
- antifungální látky farmakologie chemická syntéza MeSH
- antituberkulotika farmakologie chemická syntéza MeSH
- Aspergillus fumigatus účinky léků MeSH
- Candida účinky léků MeSH
- financování organizované MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium účinky léků MeSH
- nitrily farmakologie chemická syntéza MeSH
- pyrazinamid analogy a deriváty farmakologie chemická syntéza MeSH
- pyraziny farmakologie chemická syntéza MeSH
- Trichosporon účinky léků MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- MeSH
- pyrazinamid analogy a deriváty farmakologie chemie MeSH
- techniky in vitro MeSH
- tuberkulóza farmakoterapie MeSH
- Publikační typ
- kongresy MeSH
