Isothiocyanate-Corticosteroid Conjugates against asthma: Unity makes strength

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Respiratory Medicine

Background:

• Asthma is a chronic respiratory disease necessitating long-term treatment, often with glucocorticoids, which have adverse effects.
• Hydrogen sulfide (H2S) plays a role in airway disease pathogenesis.
• There is a need for novel asthma therapies with improved safety profiles.

Purpose of the Study:

• To design and synthesize novel multi-target molecules combining glucocorticoids and H2S-releasing moieties for asthma treatment.
• To evaluate the H2S-releasing properties, in vitro efficacy, and physicochemical stability of these hybrid molecules.
• To assess the in vivo therapeutic potential of the lead compound in an experimental asthma model.

Main Methods:

• Synthesis of novel hybrid molecules merging glucocorticoids with isothiocyanate groups.
• Screening of H2S release using amperometry and in vitro evaluation of mast cell degranulation.
• Assessment of physicochemical properties including solubility and stability at physiological pH and in BSA.
• In vivo evaluation of the lead compound (5c) in a mouse model of asthma.

Main Results:

• Novel hybrid molecules were successfully synthesized, demonstrating H2S-releasing capabilities.
• Compound 5c exhibited favorable physicochemical properties and inhibited mast cell degranulation in vitro.
• In vivo, compound 5c effectively ameliorated all asthma features, including pulmonary inflammation and structural damage.

Conclusions:

• The synthesized hybrid molecules represent a promising new therapeutic strategy for asthma.
• Compound 5c demonstrates significant potential as a dual-action therapeutic agent for asthma, addressing both inflammation and H2S deficiency.
• This approach offers a potential alternative to conventional glucocorticoid therapy with a potentially improved safety profile.