Molecular Hybrids of Deflazacort and H2S Donors: From Bench to Potential Treatment for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder characterized by oxidative stress, chronic inflammation, and skeletal muscle degeneration. Although deflazacort is the standard treatment, its long-term use is associated with significant adverse effects. Since impaired hydrogen sulfide (H2S) signaling contributes to DMD pathogenesis, we designed five novel deflazacort−H2S donor hybrids (I−V) through a molecular hybridization strategy combining anti-inflammatory efficacy with controlled sulfide release. All hybrids showed chemical stability under physiological and acidic conditions, while serum stability varied according to the linker and donor structure. Compound IV exhibited the longest half-life and a slow, l-cysteine-dependent H2S release profile. In LPS + IFN-γ-stimulated C2C12 myotubes, compound IV reduced (i) NOx production, (ii) expression of pro-inflammatory and redox-related genes, and (iii) intracellular ROS levels. In vivo, compound IV, at half of the deflazacort dose, restored locomotor performance, providing superior protection against oxidative stress, highlighting its potential as a dose-sparing therapeutic candidate for DMD.