Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

J Med Chem. 2015 Jun 25;58(12):4998-5014. doi: 10.1021/acs.jmedchem.5b00245. Epub 2015 Jun 10.


Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cells, Cultured
  • Cricetulus
  • Humans
  • Male
  • Melatonin / analogs & derivatives*
  • Melatonin / pharmacology*
  • Models, Molecular
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neurogenesis / drug effects*
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Melatonin / agonists
  • Receptors, Melatonin / antagonists & inhibitors
  • Receptors, Melatonin / metabolism*
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology


  • Oxadiazoles
  • Receptors, Melatonin
  • Thiadiazoles
  • 1,3,4-thiadiazole
  • 1,3,4-oxadiazole
  • Melatonin