Mono- and bis-edaravone adducts formed in the presence of vanillin in an aqueous solution

Edaravone (EDA) is an antioxidant drug used for the treatment of amyotrophic lateral sclerosis. Edaravone has been shown to react with aldehydes, such as 6-formylpterin. We investigated the reaction of edaravone with vanillin (used as a model aromatic aldehyde) to evidence the reaction products formed in an aqueous solution. Mono- and bis-adducts vanillin-(edaravone)(1-2) were characterized by high-performance liquid chromatography coupled to high-resolution mass spectrometry. Kinetic analysis revealed that the bis-adduct vanillin-(edaravone)(2) formed more intensely and more rapidly than the mono-adduct vanillin-(edaravone)(1). Decay rates of 2.4 mu M/min and 3.4 mu M/min were calculated for vanillin and edaravone, respectively. The Michael addition of a second edaravone molecule onto the vanillin-(edaravone)(1) hybrid corresponds to a facile reaction compared to the initial Knoevenagel-type condensation between edaravone and vanillin. However, the bis-adduct vanillin-(edaravone)(2) can decompose in solution to provide the mono-adduct and regenerate small amounts of edaravone and vanillin. The regeneration of vanillin from vanillin-(edaravone)(2) was kinetically characterized. We compared the condensation of edaravone with fifteen aromatic aldehydes, to show that only vanillin and 3-methoxy-benzaldehyde can react easily with edaravone, the other aromatic aldehydes being less or not reactive. The study opens perspectives to apprehend the reactivity of edaravone with biologically relevant aldehydes.