Synthesis, characterization, and antioxidant activity of some Ebselen analogues

Abstract

Simple synthetic routes for several analogues of the anti-inflammatory organoselenium drug, ebselen, are described. The compounds are characterized by ¹H, ¹³C, and ⁷⁷Se NMR spectroscopy and mass spectral techniques and, in some cases, by single-crystal X-ray diffraction studies. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H₂O₂, tBuOOH, and Cum-OOH as substrates, and thiophenol (PhSH, 4-Me-C₆H₄SH) and glutathione (GSH) as cosubstrates. Density functional theory (DFT) calculations have been performed on these systems to understand the effects of various substituents on the ⁷⁷Se NMR chemical shifts; these results have been compared with the experimental data. The experimental and theoretical results suggest that the presence of a phenyl substituent on the nitrogen atom is important for the antioxidant activity of ebselen. While ebselen and its analogues are poor catalysts in aromatic thiol assays, these compounds exhibit high GPx activity when GSH is used as the cosubstrate. The poor catalytic activity of ebselen analogues in the presence of aromatic thiols such as PhSH and 4-Me-C₆H₄SH can be ascribed to the undesired thiol exchange reaction that takes place at the selenium center due to Se···O nonbonding interactions. To understand the effects of different peroxides on the catalytic activities, we have determined the initial rates at various concentrations of GSH and peroxides. These data suggest that the nature of peroxide has little effect on the catalytic efficiencies, although the initial reaction rates observed with hydrogen peroxide were found to be higher than that with tBuOOH and Cum-OOH. In contrast to the effect of peroxides, the nature of thiols appears to have a dramatic effect on the catalytic activity of ebselen and its related derivatives.