Structure-activity relationships study of isothiocyanates for H₂S releasing properties: 3-Pyridyl-isothiocyanate as a new promising cardioprotective agent

Abstract

Introduction

The gasotransmitter hydrogen sulphide (H₂S), an endogenous ubiquitous signalling molecule, is known for its beneficial effects on different mammalian systems. H₂S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury.

Methods

A library of forty-five isothiocyanates, selected for their different chemical properties, has been evaluated for its hydrogen sulfide (H₂S) releasing capacity. The obtained results allowed to correlate several factors such as steric hindrance, electronic effects and position of the substituents to the observed H₂S production. Moreover, the chemical-physical profiles of the selected compounds have been studied by an in silico approach and from a combination of the obtained results, 3-pyridyl-isothiocyanate (25) has been selected as the most promising one. A detailed pharmacological characterization of its cardioprotective action has been performed.

Results

The results herein obtained strongly indicate 3-pyridyl-isothiocyanate (25) as a suitable pharmacological option in anti-ischemic therapy. The cardioprotective effects of compound 25 were tested in vivo and found to exhibit a positive effect.

Conclusion

Results strongly suggest that isothiocyanate-based H₂S-releasing drugs, such as compound 25, can trigger a ‘‘pharmacological pre-conditioning” and could represent a suitable pharmacological option in antiischemic therapy.