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.
Authors
- Vincenzo Santagada (ORCID: https://orcid.org/0000-0001-8377-8990)
- Vincenzo Calderone (ORCID: https://orcid.org/0000-0002-1441-5421)
- Ferdinando Fiorino (ORCID: https://orcid.org/0000-0001-7357-5751)
- Giuseppe Cirino (ORCID: https://orcid.org/0000-0003-3954-4083)
- Beatrice Ulloa Severino (ORCID: https://orcid.org/0000-0002-3887-8869)
- Eva Di Maro
- Francesco Frecentese (ORCID: https://orcid.org/0000-0001-8821-2937)
- Martina Smimmo (ORCID: https://orcid.org/0000-0001-9643-7378)
- Antonia Scognamiglio (ORCID: https://orcid.org/0000-0002-4282-2788)
- Valentina Citi (ORCID: https://orcid.org/0000-0001-9261-8497)
- Rosa Sparaco (ORCID: https://orcid.org/0009-0003-4221-5560)
- Angela Corvino (ORCID: https://orcid.org/0000-0002-0617-156X)
- Giuseppe Caliendo (ORCID: https://orcid.org/0000-0002-5098-6045)
- Alma Martelli (ORCID: https://orcid.org/0000-0002-2090-7107)
- Valentina Vellecco (ORCID: https://orcid.org/0000-0002-5674-9112)
- Mariarosaria Bucci (ORCID: https://orcid.org/0000-0001-5502-4315)
- Elisabetta Panza (ORCID: https://orcid.org/0000-0003-0274-4671)
- Ivana Bello (ORCID: https://orcid.org/0000-0001-6103-8748)
- Pierfrancesco Cinque
- Veronica Casale (ORCID: https://orcid.org/0009-0004-4570-3604)
Institutions
- University of Pisa (IT)
- Ospedale Antonio Cardarelli (IT)
- Federico II University Hospital (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-09-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01067
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 0.00