Synthesis, antioxidant and structural properties of modified ebselen derivatives and conjugates†

Abstract

Ebselen is a drug in clinical trials for several diseases and degenerative conditions where oxidative stress is implicated. A series of novel ebselen analogues was synthesized, including hydroxy-, alkoxy- and aminomethylene derivatives, as well as hybrid species where the ebselen selenium atom is shared with other potent antioxidant structures, such as cyclic selenenyl sulfide, cyclic seleninate ester and spirodioxyselenurane moieties. Conjugates of ebselen with cholesterol, prednisolone and the radical inhibitor BHT were also prepared. The products were tested for antioxidant activity in an NMR-based assay by measuring the rate of consumption of benzyl thiol or the production of dibenzyl disulfide in the presence of hydrogen peroxide when catalyzed by the ebselen analogues. Activities ranged from 12 to 0.12 times that of ebselen. The oxidation of the 2-hydroxymethylene derivative of ebselen was faster than thiolysis in the initial step and the overall rate was further accelerated under basic conditions. The corresponding selenenyl sulfide analogue underwent very slow disproportionation under neutral conditions that was enhanced by the presence of a base catalyst. During investigation of possible fluxional behaviour of a bis-amide analogue, an unusual tetraphenyphosphonium salt of a tricoordinate selenium pincer anion was discovered with exceptionally potent catalytic activity, 130 times that of ebselen. In addition to rate measurements, X-ray crystallography and DFT computational methods were also employed to gain further structural and mechanistic insights.