Synthesis and characterization of novel 1,2-oxazine-based small molecules that targets acetylcholinesterase

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3618-21. doi: 10.1016/j.bmcl.2014.05.040. Epub 2014 May 21.

Abstract

Thirteen 2-oxazine-based small molecules were synthesized targeting 5-lipoxygenase (LOX), and acetylcholinesterase (AChE). The test revealed that the newly synthesized compounds had potent inhibition towards both 5-LOX and AChE in lower micro molar concentration. Among the tested compounds, the most active compound, 2-[(2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2a) showed inhibitory activity towards 5-LOX and AChE with an IC50 values of 1.88, and 2.5 μM, respectively. Further, the in silico molecular docking studies revealed that the compound 2a bound to the catalytic domain of AChE strongly with a highest CDOCKER score of -1.18 kcal/mol when compared to other compounds of the same series. Additionally, 2a showed a good lipophilicity (logP=2.66), suggesting a potential ability to penetrate the blood-brain-barrier. These initial pharmacological data revealed that the compound 2a could serve as a drug-seed in developing anti-Alzheimer's agents.

Keywords: Acetylcholinesterase; Alzheimer disease; Chemical biology; Lipoxygenase; Oxazine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Oxazines / chemical synthesis
  • Oxazines / chemistry
  • Oxazines / pharmacology*
  • Phthalimides / chemical synthesis
  • Phthalimides / chemistry
  • Phthalimides / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)-1H-isoindole-1,3(2H)-dione
  • Cholinesterase Inhibitors
  • Lipoxygenase Inhibitors
  • Oxazines
  • Phthalimides
  • Small Molecule Libraries
  • Arachidonate 5-Lipoxygenase
  • Acetylcholinesterase