Synthesis, antimycobacterial, antifungal and photosynthesis-inhibiting activity of chlorinated N-phenylpyrazine-2-carboxamides

• Published in: Molecules (Basel, Switzerland) Switzerland), 2010-11, Vol.15 (12), p.8567-8581
• Main Authors: Dolezal, Martin, Zitko, Jan, Osicka, Zdenek, Kunes, Jiri, Vejsova, Marcela, Buchta, Vladimir, Dohnal, Jiri, Jampilek, Josef, Kralova, Katarina
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biological activity; Chemistry; Chlorine; Chloroplasts; Chloroplasts - metabolism; Electronic mail systems; Hydrocarbons; Hydrocarbons, Chlorinated - chemical synthesis; Hydrocarbons, Chlorinated - chemistry; Hydrocarbons, Chlorinated - pharmacology; in vitro antifungal activity; in vitro antimycobacterial activity; lipophilicity; Molecular Structure; Mycobacterium tuberculosis - growth & development; PET inhibition; Pharmacy; Photosynthesis; Photosynthesis - drug effects; Pyrazinamide - analogs & derivatives; Pyrazinamide - chemical synthesis; Pyrazinamide - chemistry; Pyrazinamide - pharmacology; pyrazinecarboxamides; spinach chloroplasts; Spinacia oleracea - metabolism; Structure-Activity Relationship; structure–activity relationships; Trichophyton - growth & development; Tuberculosis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules15128567

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.