New melatonin-cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection

Future Med Chem. 2015;7(15):1961-9. doi: 10.4155/fmc.15.99. Epub 2015 Oct 23.


Background: Neurodegenerative diseases share many pathological pathways, such as abnormal protein aggregation, mitochondrial dysfunction, extensive oxidative stress and neuroinflammation. Cells have an intrinsic mechanism of protection, the Nrf2 transcriptional factor, known as the master regulator of redox homeostasis.

Results: Based on the common features of these diseases we have designed a multi-target hybrid structure derived from melatonin and ethyl cinnamate. The obtained derivatives were Nrf2 inducers and potent-free radical scavengers. These new compounds showed a very interesting neuroprotective profile in several in vitro models of oxidative stress, Alzheimer's disease and brain ischemia.

Conclusion: We have designed a new hybrid structure with complementary activities. We have identified compound 5h as an interesting Nrf2 inducer, very potent antioxidant and neuroprotectant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cinnamates / chemistry
  • Cinnamates / pharmacology*
  • Humans
  • Melatonin / chemistry
  • Melatonin / pharmacology*
  • Molecular Structure
  • NF-E2-Related Factor 2 / metabolism*
  • Neurodegenerative Diseases / drug therapy*
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • Rats
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship


  • Antioxidants
  • Cinnamates
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Melatonin