• H2S-donors
• H2S-releasing
• hypertension

Hydrogen sulphide (H2S) is emerging as an important endogenous modulator, which exhibits the beneficial effects of nitric oxide (NO) on the cardiovascular (CV) system, without producing toxic metabolites. H2S exhibits the antioxidant properties of inorganic and organic sulphides, behaving as a scavenger of reactive oxygen species.
H2S is biosynthesized in mammalian tissues by cystathionine--synthase (CBS) and cystathionine--lyase (CSE) that is the main source of H2S in the CV.
H2S trigger other important effects and the activation of ATP-sensitive potassium channel (KATP) accounts for its vasorelaxing and cardioprotective effects. Furthermore, H2S inhibits smooth muscle proliferation and platelet aggregation. In non-CV systems, H2S regulates the functions of the central nervous system, as well as respiratory, gastroenteric, and endocrine systems. Conversely, H2S deficiency contributes to the pathogenesis of hypertension. Likewise, impairment of H2S biosynthesis is involved in CV complications associated with diabetes mellitus.
Many experiments suggest a cross-talk between the H2S and the endothelial NO pathways. In particular, recent observations indicate a possible pathogenic link between deficiencies of H2S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H2S have led several authors to look at this mediator as ‘‘the new NO’’, giving attractive opportunities to develop innovative classes of drugs.
NaHS is the prototypical example of H2S-generating agent: it is a rapid H2S-donor and the most widely used H2S-donor for experimental purposes. However, this salt is not suitable for clinical applications, as the quick release of H2S may cause adverse effects, such as a rapid and excessive lowering of blood pressure.
For a safer and effective pharmacological administration, ideal H2S-donors should generate H2S with slower releasing rates. Organic polysulphides of garlic, such as diallyl disulphide (DADS), act as H2S-releasing compounds, with a relatively slow mechanism that requires the presence of reduced glutathione. Other examples of original synthetic H2S-releasing agents have been described in the literature, including a number of aminothiol derivatives, and the phosphinodithioate derivative GYY4137. Furthermore, some H2S-releasing chemical moieties, such as the dithiolethione, the thioamide and the isothiocyanate, have been used for synthesizing multifunctional drugs.
In this study, we report the synthesis and pharmacological evaluation of a series of new arylthioamide and aryliminothioether as “smart” H2S-releasing drugs.