HYBRIDS BETWEEN H2S-DONORS AND BETAMETHASONE 17-VALERATE OR TRIAMCINOLONE ACETONIDE: IN VITRO EFFECT IN ASTHMA TREATMENT

The standard gold treatment of inflammation in asthmatic patients is represented by glucocorticoids which are the most effective drugs for the pharmacological treatment and management of persistent asthma, leading to significative reduction of morbidity and mortality [1]. More recently, molecules able to donate H2S have been described to exert positive effect on asthma, by reducing airway eosinophil infiltration and oxidative stress, promoting a protective effect against airway epithelium and endothelium damage caused by an allergic reaction [2]. Moreover, H2S induces bronchial relaxation by activating different classes of potassium channels expressed on the surface of bronchial smooth muscle cells, helping to restore the patency of respiratory tract in acute asthma events [3]. Bearing in mind that an improved pharmacological activity and a reduced toxicity can be obtained through hybridization of different molecules, simultaneously modulating multiple targets, we designed and synthesized novel betamethasone 17-valerate and triamcinolone acetonide hybrids with well-known H2S-donor moieties. Synthesized compounds have been evaluated for the potential H2S-releasing profile both in cell-free environment and into the cytosol of bronchial smooth muscle cells (BSMCs). Different H2S releasing properties for the two hybrids 4b and 5b were investigated by computer aided Structure-Activity Relationship studies demonstrating that the steric accessibility of the isothiocyanate moiety is crucial for this effect. Furthermore, the most promising derivatives 4b and 5b have been tested for inhibitory effect on mast cell degranulation and for the ability to induce cell membrane hyperpolarization in BSMCs. Significant inhibitory effect on mast cell degranulation was assessed, resulting to reduce β-hexosaminidase release more efficiently than the corresponding native drugs. Both compounds determined a massive membrane hyperpolarization of BSMCs and proved to be 4-fold more effective compared to reference compound NS1619. These effects represent an enrichment of the pharmacological activity of the native drugs.