Novel H₂S-Releasing Bifunctional Antihistamine Molecules with Improved Antipruritic and Reduced Sedative Actions

Hydrogen sulfide (H2S) is an endogenous gasotransmitterwith anti-inflammatory actions that also reduces itching. To testwhether a combination of an antihistamine with a H2S donorhas improved antipruritic efficacy, bifunctional molecules with antihistamineand H2S-releasing pharmacophores were synthesized and tested in vitro and in vivo. H2S releasefrom the hybrid molecules was evaluated with the methylene blue andlead acetate methods, and H1-blocking activity was assessed by determiningtissue factor expression inhibition. All new compounds released H2S in a dose-dependent manner and retained histamine blockingactivity. Two compounds with the highest potency were evaluated in vivo for their antipruritic as well as sedative action;they proved to possess higher efficacy in inhibiting histamine-inducedpruritus and decreased sedative effects compared to the parent compounds(hydroxyzine and cetirizine), suggesting that they exhibit superiorantipruritic action and limited side effects that likely arise fromthe H2S-releasing moiety.