title: Synthesis, antimycobacterial activity and in vitro cytotoxicity of 5-chloro-N-phenylpyrazine-2-carboxamides.
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).
authors: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic. jan.zitko@faf.cuni.cz.
authors: Jan
authors: J
authors: Zitko
authors: Barbora
authors: B
authors: Servusová
authors: Pavla
authors: P
authors: Paterová
authors: Jana
authors: J
authors: Mandíková
authors: Vladimír
authors: V
authors: Kubíček
authors: Radim
authors: R
authors: Kučera
authors: Veronika
authors: V
authors: Hrabcová
authors: Jiří
authors: J
authors: Kuneš
authors: Ondřej
authors: O
authors: Soukup
authors: Martin
authors: M
authors: Doležal
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: C111084:5-chloropyrazinamide; D000935:Antifungal Agents; D000995:Antitubercular Agents; D011718:Pyrazinamide