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Substituted N-phenylpyrazine-2-carboxamides, Their Synthesis, Hydro-lipophilic Properties and Evaluation of Their Antimycobacterial, Antifungal and Photosynthesis-inhibiting Activity
1 , 2 , 3 , 4, 5 , 3 , 3 , 6 , * 3
1  Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina Ch-2, 84215 Bratislava, Slovakia
2  Department of Clinical Microbiology, Charles University Medical School and Teaching Hospital, Sokolska 581, Hradec Kralove 500 05, Czech Republic
3  Dept. of Medicinal Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, 500 05 Hradec Kralove, 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  Bioveta a.s., Komenskeho 212, 683 23 Ivanovice na Hane, Czech Republic

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 and characterized. The results of in vitro antimycobacterial screening indicated some interesting antimycobacterial activity. 6-Chloro-N-(4-chlorophenyl)pyrazine-2-carboxamide (6) has shown the highest activity against Mycobacterium tuberculosis strain H37Rv (65% inhibition at 6.25 μg mL-1). 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 (16) (MIC = 62.5 μmol mL-1). 6-Chloro-5-tert-butyl-N-(4-chlorophenyl)pyrazine-2-carboxamide (8) was the most active in the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts (IC50 = 43.0 μmol mL-1). The compounds were analyzed using RP-HPLC to determine lipophilicity. Optimal log P value for studied series was not confirmed.For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed, as well as their structure-activity relationships (SAR).
Keywords: Pyrazinecarboxamides; Lipophilicity; In vitro antimycobacterial activity; In vitro antifungal activity; Spinach chloroplasts; PET inhibition; Structure-activity relationships.