title: Synthesis and antimycobacterial evaluation of 5-alkylamino-N-phenylpyrazine-2-carboxamides.
abstract: Substitution of chlorine in 5-chloro-N-phenylpyrazine-2-carboxamide (1) with simple n-alkylamines yielded a series of 5-alkylamino-N-phenylpyrazine-2-carboxamides (propylamino to octylamino derivatives), which possessed similar or increased activity against Mycobacterium tuberculosis H37Rv compared to parent 5-chloro derivative (1), with MIC ranging from 2.5 to 12.2 μM. 5-Butylamino to 5-heptylamino derivatives exerted similar activity also against Mycobacterium kansasii. Importantly, the substitution led also to significant decrease of in vitro cytotoxicity in HepG2 cell line. 5-Heptylamino-N-phenylpyrazine-2-carboxamide (1e) exerted MIC=2.5 μM (M.tbc) and IC50 >250 μM (HepG2). Further modification of alkylamino chain with terminal methoxy or hydroxy group lead to compounds with decreased or none activity, the decrease was proportional to the decrease of lipophilicity. 5-(2-Phenylethylamino) and 5-(3-phenylpropylamino) derivatives were also of decreased activity. On contrary to alkylamino derivatives derived from 1, alkylamino derivatives derived from 5-chloro-N-2-chlorophenylpyrazine-2-carboxamide (2) possessed substantially decreased or none activity. None of the prepared compounds was active against Mycobacterium avium.
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic. Electronic address: jan.zitko@faf.cuni.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Zitko
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Servusová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Janoutová
authors.affiliation: Department of Clinical Microbiology, University Hospital, Sokolská 581, Hradec Králové 500 05, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Paterová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Mandíková
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojárov 10, Bratislava 832 32, Slovakia.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Garaj
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
authors.forename: Marcela
authors.initials: M
authors.lastname: Vejsová
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Marek
authors.affiliation: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Doležal
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D011718:Pyrazinamide / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D011718:Pyrazinamide
keywords: Alkylamino derivatives; Antituberculars; Cytotoxicity; Permeability; Pyrazinamide