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• Dolezal, M
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Molecules 2010, 15(12), 8567-8581; doi:10.3390/molecules15128567

Article

Synthesis, Antimycobacterial, Antifungal and Photosynthesis-Inhibiting Activity of Chlorinated N-phenylpyrazine-2-carboxamides ^†

Martin Dolezal ^1,* , Jan Zitko ¹ , Zdenek Osicka ² , Jiri Kunes ¹ , Marcela Vejsova ¹ , Vladimir Buchta ³ , Jiri Dohnal ^4,5 , Josef Jampilek ^4,5  and Katarina Kralova ⁶

¹ Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic ² Bioveta a.s., Komenskeho 212, 683 23 Ivanovice na Hane, Czech Republic ³ Department of Clinical Microbiology, Faculty of Medicine and University Hospital, Charles University in Prague, Sokolska 581, Hradec Kralove, 500 05, Czech Republic ⁴ Zentiva k.s., U Kabelovny 130, 102 37 Prague 10, Czech Republic ⁵ Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1/3, 61242 Brno, Czech Republic ⁶ 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)

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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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