Synthesis and biological activity of 5-alkyl-6-(alkylsulfanyl)- or 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides and corresponding thioamides.
Nucleophilic substitution of chlorine in 5-alkyl-6-chloropyrazine-2-carboxamides with various alkyl and arylthiolates afforded 20 5-alkyl-6-(alkylsulfanyl)- and 5-alkyl-6-(arylsulfanyl)pyrazine-2-carboxamides. The reaction of the amides with Lawesson's reagent yielded the corresponding thioamides. The assessment of in vitro antimycobacterial and antifungal activity of the compounds was carried out. In both series, the antimycobacterial activity increases with increasing molecular weight of the alkylsulfanyl group in position 6 of the pyrazine ring. Thioamides exhibited higher activity than the corresponding amides. 5-Butyl-6-(phenylsulfanyl)pyrazine-2-carbothioamide (2j) possessed the highest activity (91% inhibition) against Mycobacterium tuberculosis and also the highest lipophilicity (log P = 4.95). Only a poor in vitro antifungal effect was noted in 5-butyl-6-(butylsulfanyl)pyrazine-2-carboxamide (1i) and 6-(ethylsulfanyl)-5-isobutylpyrazine-2-carbothioamide (2q) against Trichophyton mentagrophytes and Absidia corymbifera.
Krinková
Jana
J
Department of Pharmaceutical Chemistry and Drug Control, Charles University in Prague, Faculty of Pharmacy, Hradec Králové, Czech Republic. krinkova@faf.cuni.cz
Dolezal
Martin
M
Hartl
Jirí
J
Buchta
Vladimír
V
Pour
Milan
M
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000138:chemical synthesis* / Q000494:pharmacology
D000890:Anti-Infective Agents; D000935:Antifungal Agents; D011719:Pyrazines; D013854:Thioamides