Synthesis of Novel Pyrazinamide Derivatives Based on 3-Chloropyrazine-2-carboxamide and Their Antimicrobial Evaluation.
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.
Department of Biological and Medical Sciences, Teaching and Research Center of Charles University, Faculty of Pharmacy in Hradec Kralove, Charles University, Zborovska 2089, Hradec Kralove 50003, Czech Republic. jando6aa@faf.cuni.cz.
Ondrej
O
Jandourek
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203/8, Hradec Kralove 50005, Czech Republic. tauchmam@faf.cuni.cz.
Marek
M
Tauchman
Department of Clinical Microbiology, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 50005, Czech Republic. pavla.paterova@fnhk.cz.
Pavla
P
Paterova
Department of Biological and Medical Sciences, Teaching and Research Center of Charles University, Faculty of Pharmacy in Hradec Kralove, Charles University, Zborovska 2089, Hradec Kralove 50003, Czech Republic. konecna@faf.cuni.cz.
Klara
K
Konecna
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203/8, Hradec Kralove 50005, Czech Republic. navratl2@faf.cuni.cz.
Lucie
L
Navratilova
Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203/8, Hradec Kralove 50005, Czech Republic. kubicek@faf.cuni.cz.
Vladimir
V
Kubicek
Department of Pharmaceutical Technology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203/8, Hradec Kralove 50005, Czech Republic. holao3aa@faf.cuni.cz.
Ondrej
O
Holas
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203/8, Hradec Kralove 50005, Czech Republic. zitkj3aa@faf.cuni.cz.
Jan
J
Zitko
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203/8, Hradec Kralove 50005, Czech Republic. dolezalm@faf.cuni.cz.
Martin
M
Dolezal
D000577:Amides / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011718:Pyrazinamide / Q000138:chemical synthesis* / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000935:Antifungal Agents; D000995:Antitubercular Agents; D011719:Pyrazines; D011718:Pyrazinamide
antibacterials; antifungals; benzylamines; cytotoxicity; microwave-assisted; pyrazinamide; tuberculosis