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Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides
Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic
Department of Clinical Microbiology, University Hospital, Sokolská 581, Hradec Králové 500 05, Czech Republic
Biomedical Research Center, Sokolská 581, Hradec Králové 500 05, Czech Republic
Department of Chemistry, Faculty of Science, University of Hradec Králové, Jana Koziny 1237, Hradec Králové 500 05, Czech Republic
* Author to whom correspondence should be addressed.
Received: 15 November 2013; in revised form: 26 November 2013 / Accepted: 26 November 2013 / Published: 2 December 2013
Abstract: 5-Chloropyrazinamide (5-Cl-PZA) is an inhibitor of mycobacterial fatty acid synthase I with a broad spectrum of antimycobacterial activity in vitro. Some N-phenylpyrazine-2-carboxamides with different substituents on both the pyrazine and phenyl core possess significant in vitro activity against Mycobacterium tuberculosis. To test the activity of structures combining both the 5-Cl-PZA and anilide motifs a series of thirty 5-chloro-N-phenylpyrazine-2-carboxamides with various substituents R on the phenyl ring were synthesized and screened against M. tuberculosis H37Rv, M. kansasii and two strains of M. avium. Most of the compounds exerted activity against M. tuberculosis H37Rv in the range of MIC = 1.56–6.25 µg/mL and only three derivatives were inactive. The phenyl part of the molecule tolerated many different substituents while maintaining the activity. In vitro cytotoxicity was decreased in compounds with hydroxyl substituents, preferably combined with other hydrophilic substituents. 5-Chloro-N-(5-chloro-2-hydroxyphenyl)pyrazine-2-carboxamide (21) inhibited all of the tested strains (MIC = 1.56 µg/mL for M. tuberculosis; 12.5 µg/mL for other strains). 4-(5-Chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (30) preserved good activity (MIC = 3.13 µg/mL M. tuberculosis) and was rated as non-toxic in two in vitro models (Chinese hamster ovary and renal cell adenocarcinoma cell lines; SI = 47 and 35, respectively).
Keywords: pyrazinamide; 5-chloropyrazinamide; anilides; antimycobacterial activity; cytotoxicity
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Zitko, J.; Servusová, B.; Paterová, P.; Mandíková, J.; Kubíček, V.; Kučera, R.; Hrabcová, V.; Kuneš, J.; Soukup, O.; Doležal, M. Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides. Molecules 2013, 18, 14807-14825.
Zitko J, Servusová B, Paterová P, Mandíková J, Kubíček V, Kučera R, Hrabcová V, Kuneš J, Soukup O, Doležal M. Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides. Molecules. 2013; 18(12):14807-14825.
Zitko, Jan; Servusová, Barbora; Paterová, Pavla; Mandíková, Jana; Kubíček, Vladimír; Kučera, Radim; Hrabcová, Veronika; Kuneš, Jiří; Soukup, Ondřej; Doležal, Martin. 2013. "Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides." Molecules 18, no. 12: 14807-14825.