Alkyl Chain‐Functionalized Nitronyl Nitroxide Radicals: Structure‐Microenvironment Effects on Thiol Kinetics and Dual Antioxidant Behavior

Radical reactivity can be modulated through structural and microenvironmental control, thereby representing an important challenge in the design of redox‐active systems. In this study, an alkyl chain‐functionalized series of nitronyl nitroxide (NN) radicals designed and synthesized by varying their amphiphilic character. Subsequently, their thiol‐based reactivity and microenvironment accessibility, along with antioxidant profile, were investigated. Radical behavior was monitored in aqueous media and sodium dodecyl sulfate (SDS) micelles. Accessibility properties and micellar partitioning of all radicals were evaluated in a concentration‐dependent manner, using electron paramagnetic resonance (EPR). Glutathione (GSH) reactivity and quantitative EPR kinetic analysis revealed that the reduction rate constants systematically decrease with increasing alkyl chain length, leading to the formation of diamagnetic hydroxylamine species. In the presence of SDS, the reactivity of NN derivatives with GSH was dramatically suppressed, confirming the protection of the nitroxide center from thiol reduction. The NN‐functionalized derivatives displayed a dual antioxidant mechanism, based on electron transfer and hydrogen atom transfer (HAT). The limited superoxide scavenging and pro‐oxidant effects indicated radical‐specific selectivity under single‐electron transfer (SET) conditions. Notably, all derivatives exhibited pronounced inhibition of lipid peroxidation, confirming their effectiveness in chain‐breaking antioxidant activity and rendering them competitive agents in targeted therapeutics and stress‐based pathologies.