Design and synthesis of H 2 S-donor hybrids: A new treatment for Alzheimer's disease?

Eur J Med Chem. 2019 Dec 15;184:111745. doi: 10.1016/j.ejmech.2019.111745. Epub 2019 Sep 27.


Hydrogen sulphide (H2S) is an endogenous gasotransmitter, largely known as a pleiotropic mediator endowed with antioxidant, anti-inflammatory, pro-autophagic, and neuroprotective properties. Moreover, a strong relationship between H2S and aging has been recently identified and consistently, a significant decline of H2S levels has been observed in patients affected by Alzheimer's disease (AD). On this basis, the use of H2S-donors could represent an exciting and intriguing strategy to be pursued for the treatment of neurodegenerative diseases (NDDs). In this work, we designed a small series of multitarget molecules combining the rivastigmine-scaffold, a well-established drug already approved for AD, with sulforaphane (SFN) and erucin (ERN), two natural products deriving from the enzymatic hydrolysis of glucosinolates contained in broccoli and rocket, respectively, endowed both with antioxidant and neuroprotective effects. Notably, all new synthetized hybrids exhibit a H2S-donor profile in vitro and elicit protective effects in a model of LPS-induced microglia inflammation. Moreover, a decrease in NO production has been observed in LPS-stimulated cells pre-treated with the compounds. Finally, the compounds showed neuroprotective and antioxidant activities in human neuronal cells. The most interesting compounds have been further investigated to elucidate the possible mechanism of action.

Keywords: Alzheimer's disease; Erucin; Hydrogen sulphide; Multitarget approach; Sulforaphane.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Hydrogen Sulfide / chemical synthesis
  • Hydrogen Sulfide / chemistry
  • Hydrogen Sulfide / pharmacology*
  • Isothiocyanates / chemical synthesis
  • Isothiocyanates / chemistry
  • Isothiocyanates / pharmacology*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Mice
  • Microglia / drug effects
  • Molecular Structure
  • Neurons / drug effects
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Rivastigmine / chemical synthesis
  • Rivastigmine / chemistry
  • Rivastigmine / pharmacology*
  • Structure-Activity Relationship
  • Sulfides / chemical synthesis
  • Sulfides / chemistry
  • Sulfides / pharmacology
  • Thiocyanates / chemical synthesis
  • Thiocyanates / chemistry
  • Thiocyanates / pharmacology


  • Antioxidants
  • Isothiocyanates
  • Lipopolysaccharides
  • Neuroprotective Agents
  • Sulfides
  • Thiocyanates
  • erucin
  • sulforaphane
  • Rivastigmine
  • Hydrogen Sulfide