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

M.   L.N.   Dubuisson; J.-   F.   Rees; J.      Marchand-Brynaert

doi:10.2174/1389557043403927

Abstract

Coelenteramine (2-amino-1,4-pyrazine derivative), one of the metabolites of the oxidative degradation of coelenterazine (imidazolopyrazinone derivative), is endowed with excellent antioxidative properties towards ROS / RNS, like its mother-compound. This crucial discovery, made during the study of natural bioluminescent compounds (luciferins), has stimulated the development of synthetic aminopyrazine derivatives as new leads in medicinal chemistry in the field of antioxidant-based therapies. Synthetic approaches, theoretical evaluation, radical scavenging properties in acellular and cellular tests, and in vivo evaluation are described, and illustrated with representative aminopyrazines. Tested compounds were inhibitors of lipid peroxidation and good quenchers of peroxynitrite. They efficiently protect isolated LDL against radical-induced damages. They prevent cell constituents (membranes, DNA) against injuries by various oxidative stressors (UV irradiation, hydroperoxide treatment, oxidized LDL toxicity). Lastly, aminopyrazines are remarkably active in the “hamster cheek pouch” assay (in vivo protection against ischemia-reperfusion damages).

Keywords: 2-amino-1, 4-pyrazine derivatives, 2,6-diamino-1, antioxidants, radical scavengers, reactive oxygen species (ros), reactive nitrogen species (rns), cellular oxidative stress, ischemia-reperfusion