Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution

• Published in: Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (2), p.476-479
• Main Authors: Zitko, Jan, Paterová, Pavla, Kubíček, Vladimír, Mandíková, Jana, Trejtnar, František, Kuneš, Jiří, Doležal, Martin
• Format: Article
• Language: English
• Subjects: antibacterial properties; Antitubercular Agents - chemical synthesis; Antitubercular Agents - pharmacology; Benzylamines - chemistry; Cells, Cultured; Cytotoxicity; Data processing; hepatotoxicity; Humans; hydrophobicity; Inhibitory Concentration 50; Microbial Sensitivity Tests; Minimum inhibitory concentration; Molecular Structure; Mycobacterium - drug effects; Mycobacterium avium; Mycobacterium kansasii; Mycobacterium tuberculosis; pyrazinamide; Pyrazinamide - chemical synthesis; Pyrazinamide - pharmacology; reversed-phase high performance liquid chromatography
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.052

A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium. The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino)pyrazine-2,5-dicarbonitriles with various substituents on the phenyl ring. RP-HPLC method was used to determine the lipophilicity of the prepared compounds. Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC=6.25–12.5μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5–25μg/mL. Although not the most active, 4-NH₂ substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI=5.5 and SI >21.