Amide-based glutathione peroxidase mimics: effect of secondary and tertiary amide substituents on antioxidant activity

Abstract

Sec or terts: A series of sec- and tert-amide substituted diselenides have been synthesised as synthetic mimics of glutathione peroxidase (GPx), characterized, and studied for their antioxidant activities using H₂O₂, Cum-OOH, and tBuOOH as substrates and PhSH as thiol co-substrate. The substitution at the free NH group of the amide moiety in the sec-amide based diselenides is shown to enhance the GPx activity. A series of secondary and tertiary amide-substituted diselenides were synthesized and studied for their GPx-like antioxidant activities using H₂O₂, Cum-OOH, and tBuOOH as substrates and PhSH as thiol co-substrate. The effect of substitution at the free -NH group of the amide moiety in the sec-amide-based diselenides on GPx activity was analyzed by detailed experimental and theoretical methods. It is observed that substitution at the free -NH group significantly enhances the GPx-like activities of the sec-amide-based diselenides, mainly by reducing the Se···O nonbonded interactions. The reduction in strength of the Se···O interaction upon introduction of N,N-dialkyl substituents not only prevents the undesired thiol exchange reactions, but also reduces the stability of selenenyl sulfide intermediates. This leads to a facile disproportionation of the selenenyl sulfide to the corresponding diselenide, which enhances the catalytic activity. The mechanistic investigations indicate that the reactivity of diselenides having sec- or tert-amide moieties with PhSH is extremely slow; indicating that the first step of the catalytic cycle involves the reaction between the diselenides and peroxide to produce the corresponding selenenic and seleninic acids.