1,2,4-Thiadiazolidin-3,5-diones as novel hydrogen sulfide donors

Eur J Med Chem. 2018 Jan 1:143:1677-1686. doi: 10.1016/j.ejmech.2017.10.068. Epub 2017 Nov 11.

Abstract

Hydrogen sulfide (H2S) is an endogenous modulator that plays significant physio-pathological roles in several biological systems. In this research field there is a large interest in developing selective CBS and CSE inhibitors and H2S releasing moieties, that could be either used as therapeutic agents or linked to known drugs. One of the major problem is the limited availability of chemicals that ensure a controlled release of H2S in vitro as well in vivo. Aiming to obtain novel H2S donors, whose release properties could be appropriately modulated, we have synthesized a series of 1,2,4-thiadiazolidine-3,5-diones (THIA 1-10) as innovative donors that could release H2S in controlled manner. All the synthesized compounds were evaluated for their H2S releasing properties by an amperometric approach and for their vasorelaxant ability on aorta rings. In order to rationalize the obtained results, a detailed study on the release mechanism has been performed using the most efficient H2S donor, THIA 3 (Cmax 65.4 μM and EC50 1.7 μM).

Keywords: 1,2,4-Thiadiazolidine-3,5-diones; H(2)S donors; Hydrogen sulfide; Release mechanism.

MeSH terms

  • Animals
  • Aorta / chemistry
  • Aorta / metabolism
  • Cystathionine beta-Synthase / antagonists & inhibitors*
  • Cystathionine beta-Synthase / metabolism
  • Cystathionine gamma-Lyase / antagonists & inhibitors*
  • Cystathionine gamma-Lyase / metabolism
  • Dose-Response Relationship, Drug
  • Hydrogen Sulfide / analysis
  • Hydrogen Sulfide / metabolism*
  • Male
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology*

Substances

  • Thiazolidinediones
  • Cystathionine beta-Synthase
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide