title: Synthesis and antimycobacterial evaluation of N-substituted 3-aminopyrazine-2,5-dicarbonitriles.
abstract: A series of 14 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and two types of Mycobacterium avium. The series comprised of N-substituted 3-aminopyrazine-2,5-dicarbonitriles derived from 3-chloropyrazine-2,5-dicarbonitrile by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines, cycloalkylamines and heterocyclic amines). Noteworthy antimycobacterial activity against M. tuberculosis was found among the alkylamino derivatives, for example, 3-(heptylamino)pyrazine-2,5-dicarbonitrile inhibited M. tuberculosis at MIC=51 μmol/L. 3-(Hexylamino)pyrazine-2,5-dicarbonitrile inhibited M. kansasii at MIC=218 μmol/L. Basic structure-activity relationships are discussed. A comparison between calculated and experimentally determined lipophilicity parameters within the series is included.
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. jan.zitko@faf.cuni.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Zitko
authors.forename: Josef
authors.initials: J
authors.lastname: Jampílek
authors.forename: Lukáš
authors.initials: L
authors.lastname: Dobrovolný
authors.forename: Michaela
authors.initials: M
authors.lastname: Svobodová
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* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D019909:Mycobacterium kansasii / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide