2,6-Diamino-3,5-diaryl-1,4-pyrazine Derivatives as Novel Antioxidants

Abstract

The coupling of arylboronic acids with 2,6-diamino-3,5-dibromo-1,4-pyrazine (6) gave 2,6-diamino-3,5-diaryl-1,4-pyrazines (7). The reaction of 7 with methyl glyoxal in aqueous EtOHHCl led to the N,N'-disubstituted products 8, instead of the expected bicyclic imidazolopyrazinones 1. The 2,6-bis[1-(ethoxycarbonyl)-ethylamino]-3,5-diaryl-1,4-pyrazines 8 are powerful inhibitors of the AAPH-induced linoleate peroxidation.Recently we became interested in the synthesis of imidazolopyrazinone derivatives 1 (Scheme 1) as potential antioxidants useful in medicinal chemistry for the design of drugs against injuries caused by oxidative stress. 1,2 Coelenterazine (CLZ), a naturally occurring imidazolopyrazinone of marine origin (1: R 1 = p-HO-Ph; R 2 = PhCH 2 ; R 3 = p-HO-PhCH 2 ; R 4 = H), is the luminescent substrate of enzymes (luciferases) producing light in the presence of oxygen. 3 Synthetic derivatives of coelenterazine can be obtained by condensing 2-amino-1,4-pyrazine precursors 2 with a-keto-aldehydes 3 (or the corresponding acetals) in aqueous acidic medium (Scheme 1). 4 Two routes have been exploited for the synthesis of aminopyrazines 2 equipped with natural or non-natural substituents R 1 , R 2 , and R 4 : (i) condensation of 1,2-propanedione-2-oxime derivatives with 2-amino-propionitrile compounds to form the substituted heterocycles; 5 (ii) functionalization of bromo-aminopyrazine derivatives via a Suzuki coupling reaction with boronic acid derivatives. 6 This last method was exemplified in our group for the preparation of a series of 3,5-diaryl-2-amino-1,4-pyrazines 2 (R 4 = H) and the related 6,8-diaryl-imidazolopyrazinones 1 (R 1 and R 2 = aryl; R 4 = H) which reveal to be powerful antioxidants. 1b

Discovery and Validation of a New Family of Antioxidants: The Aminopyrazine Derivatives

“…Thus, the catechol derivatives 2, 6 and 7 (Table 4), tested at 2.5 µM, induced a lag phase of 250-270 min. The diamine-diphenol derivative 9 was similarly active [44]. Interestingly, the diamine compound 8 devoid of phenol motif was also able to delay the onset of lipid peroxidation, with the same activity as Trolox, a water-soluble analog of vitamin E (lag phase of 100-110 min).…”

“…In the particular case of 2,6-(diamino)pyrazine derivatives (OH-free precursors), N-derivatization resulted from treatment with methyl glyoxal in ethanol-HCl ( Fig. (5); Table 1) [44].…”

“…(3)) [44]; the precursor was obtained by substitution of 2,6-(dichloro)pyrazine with sodium azide and subsequent reduction by hydrogenation. Then, bromination and organometallic coupling of boronic acids, as before, furnished symmetrically substituted compounds (Table 1).…”

In vitro and in vivo studies of 6,8-(diaryl)imidazo[1,2-a]pyrazin-3(7H)-ones as new antioxidants

“…[32][33][34][35] Amide 2b was independently prepared from 2-ami- no-5-[p-(t-butyldimethylsilyloxy)-phenyl]-1,4-pyrazine 3d (see Scheme 2), 36 by benzoylation (benzoyl chloride, pyridine, reflux) followed by deprotection of the phenol moiety (Bu 4 NF, THF, 20°C). For HPLC analysis all compounds and benzoic acid (4) were dissolved in acetonitrile (ACN)-EtOH (96:4, v/v) at 8 Â 10 À5 M final concentration.…”

Pb(NO3)2 Mediated Synthesis of Pyrazine

“…Furthermore, pyrazine derivatives have been used as antioxidation compounds. 5,7,8 In recent year, aromatization of 1,4-dihydropyrazine occupies an important place in chemistry and pharmacology. Aromatization of 1,4-dihydropyrazine occupies an important place in chemistry and pharmacology.…”