Synthesis of imidazo[1,2-a]quinoxalines by double Groebke reactions and inhibitory effects on radicals and DNA oxidation

Abstract

The o-phenylenediamine, aldehyde, and 2,4,4-trimethylpentan-2-yl isocyanide performed a Groebke 3CR to afford 2-aminoquinoxaline, which can react with an aldehyde and t-butyl isocyanide via another Groebke 3CR to give imidazo[1,2-a]quinoxaline. Exchanging two aldehydes in the sequential Groebke 3CR led to a couple of imidazo[1,2-a]quinoxaline isomer, in which the aldehyde moiety located at 2- or 4-position. The ferrocenyl group at 4-position in imidazo[1,2-a]quinoxaline was found to be active in trapping galvinoxyl radical, while the phenolic hydroxyl group at 2-position played a synergistic role with 4-ferrocenyl or 4-flavonyl group in scavenging 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH). In addition, 4-ferrocenyl with N,N-dimethylaminophenyl group at 2-position was able to quench 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+). Moreover, the combination of 4-ferrocenyl with 2-phenyl group (bearing para-N,N-dimethylamino or hydroxyl group) exhibited high inhibitory effect on DNA oxidation induced by 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH).