Asthma is a major noncommunicable disease, affecting both children and adults, and represents one of the major causes leading to high health care costs due to the need for chronic pharmacological treatments. The standard gold therapy of inflammation in asthmatic patients involves the use of glucocorticoids even if their chronic use is often related to serious adverse effects. Growing evidence suggests the biological relevance of hydrogen sulfide (H2S) in the pathogenesis of airway diseases. Hence, aiming to associate the beneficial effects of steroidal anti-inflammatory drugs (SAIDs) to H2S biological activity, we designed and synthesized novel multi-target molecules by chemically combining a group of glucocorticoids, usually employed in asthma treatment, with an isothiocyanate moiety, well-known for its H2S releasing properties. Firstly, the synthesized compounds have been screened for their H2S-releasing profile using an amperometric approach and for their in vitro effects on the degranulation process, using RBL-2H3 cell line. The physicochemical profile, in terms of solubility, chemical and enzymatic stability of the newly hybrid molecules, has been assessed at different physiological pH values and in esterase-rich medium (bovine serum albumin, BSA). The selected compound 5c, through both its corticosteroid and H2S releasing component, has been evaluated in vivo in experimental model of asthma. The compound 5c inhibited in vivo all asthma features with a significative effect on the restoration of pulmonary structure and reduction of lung inflammation.
Keywords: Asthma; Hybrids; Multi-target molecules; Steroidal anti-inflammatory drugs; hydrogen sulfide; isothiocyanates.
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