title: Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution.
abstract: 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=6.25-12.5 μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5-25 μg/mL. Although not the most active, 4-NH(2) substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI=5.5 and SI >21.
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic. jan.zitko@faf.cuni.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Zitko
authors.forename: Pavla
authors.initials: P
authors.lastname: Paterová
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kubíček
authors.forename: Jana
authors.initials: J
authors.lastname: Mandíková
authors.forename: František
authors.initials: F
authors.lastname: Trejtnar
authors.forename: Jiří
authors.initials: J
authors.lastname: Kuneš
authors.forename: Martin
authors.initials: M
authors.lastname: Doležal
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001596:Benzylamines / Q000737:chemistry*; D002478:Cells, Cultured; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects*; D011718:Pyrazinamide / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001596:Benzylamines; D011718:Pyrazinamide