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

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• 作者：Jan Zitko ; Barbora Servusová-Vaňásková ; Pavla Paterová…
• 关键词：anilide ; anti ; mycobacterial activity ; cytotoxicity in vitro ; lipophilicity ; pyrazinoic acid
• 刊名：Chemical Papers
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：70
• 期：5
• 页码：649-657
• 全文大小：
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry/Food Science, general; Industrial Chemistry/Chemical Engineering; Biochemistry, general; Medicinal Chemistry; Materials Science, general; Biotechnology;
• 出版者：Springer International Publishing
• ISSN：1336-9075
• 卷排序：70

文摘

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 tuberculosis H37Rv 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 kansasii with 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.