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Synthesis, Antimycobacterial, Antifungal and Photosynthesis-Inhibiting Activity of Chlorinated N-phenylpyrazine-2-carboxamides †
Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic
Bioveta a.s., Komenskeho 212, 683 23 Ivanovice na Hane, Czech Republic
Department of Clinical Microbiology, Faculty of Medicine and University Hospital, Charles University in Prague, Sokolska 581, Hradec Kralove, 500 05, Czech Republic
Zentiva k.s., U Kabelovny 130, 102 37 Prague 10, Czech Republic
Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1/3, 61242 Brno, Czech Republic
Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska Dolina CH-2, 842 15 Bratislava, Slovak Republic
Preliminary results were presented at the Fourteenth Electronic Conference on Synthetic Organic Chemistry (ECSOC-14, http://www.sciforum.net/presentation/380), November 1-30, 2010.
* Author to whom correspondence should be addressed.
Received: 15 November 2010; in revised form: 22 November 2010 / Accepted: 25 November 2010 / Published: 26 November 2010
(This article belongs to the Special Issue ECSOC-12
Abstract: 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.
Keywords: pyrazinecarboxamides; lipophilicity; in vitro antimycobacterial activity; in vitro antifungal activity; spinach chloroplasts; PET inhibition; structure–activity relationships
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Dolezal, M.; Zitko, J.; Osicka, Z.; Kunes, J.; Vejsova, M.; Buchta, V.; Dohnal, J.; Jampilek, J.; Kralova, K. Synthesis, Antimycobacterial, Antifungal and Photosynthesis-Inhibiting Activity of Chlorinated N-phenylpyrazine-2-carboxamides †. Molecules 2010, 15, 8567-8581.
Dolezal M, Zitko J, Osicka Z, Kunes J, Vejsova M, Buchta V, Dohnal J, Jampilek J, Kralova K. Synthesis, Antimycobacterial, Antifungal and Photosynthesis-Inhibiting Activity of Chlorinated N-phenylpyrazine-2-carboxamides †. Molecules. 2010; 15(12):8567-8581.
Dolezal, Martin; Zitko, Jan; Osicka, Zdenek; Kunes, Jiri; Vejsova, Marcela; Buchta, Vladimir; Dohnal, Jiri; Jampilek, Josef; Kralova, Katarina. 2010. "Synthesis, Antimycobacterial, Antifungal and Photosynthesis-Inhibiting Activity of Chlorinated N-phenylpyrazine-2-carboxamides †." Molecules 15, no. 12: 8567-8581.