ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Design, synthesis and anti-mycobacterial evaluation of some new iV-phenylpyrazine-2-carboxamides

Jan Zitko, Servusová-Vanásková Barbora, Pavla Paterová, Lucie Navrátilová, František Trejtnar, Jiří Kuneš, and Martin Doležal

^aFaculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové 50005, Czech Republic

E-mail: jan.zitko@faf.cuni.cz

Abstract: N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various positions) were previously shown to possess significant biological activities in vitro, markedly anti-mycobacterial and photosynthesis-inhibiting activity. Based on structure-activity relationships (SAR) extracted from previously published series, 25 new anilides of non-substituted pyrazinoic acid (POA), 5-CH₃-POA, 6-Cl-POA, 5-tert-butyl-POA and 5-tert-butyl-6-Cl-POA were designed and synthesised. The phenyl part was substituted with simple hydrophobic substituents chosen from methyl and halogens. 5-tert-Butyl-N-(5-fluoro-2-methylphenyl)pyrazine-2- carboxamide (9), N-(3-chloro-4-methylphenyl)-5-methylpyrazine-2-carboxamide (12), 6-chloro-N- (3-chloro-4-methylphenyl)pyrazine-2-carboxamide (13) and 6-chloro-N-(5-iodo-2-methylphenyl)pyrazine-2-carboxamide (18) possessed whole cell anti-mycobacterial activity in vitro against Mycobacterium tuberculosisH37Rv with minimum inhibitory concentration (MIC) of around 10 μM. Importantly, no cytotoxicity in the HepG2 model was detected in vitro at the concentrations tested and the estimated IC₅₀ values were in hundreds of μM, indicating promising selectivity. N-(3-Chloro-4-methylphenyl)pyrazine-2-carboxamide (11) and N-(4-chloro-2-iodophenyl)pyrazine- 2-carboxamide (21) exerted significant activity against Mycobacterium kansasiiwith MIC 12.6 μM and 8.7 μM, respectively. No activity was detected against Mycobacterium avium. SAR were in accordance with those observed for the derivatives previously published.

Keywords: anilide – anti-mycobacterial activity – cytotoxicity in vitro – lipophilicity – pyrazinoic acid

Full paper is available at www.springerlink.com.

DOI: 10.1515/chempap-2015-0246

Chemical Papers 70 (5) 649–657 (2016)