Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer's disease

Bioorg Med Chem. 2018 May 1;26(8):1665-1674. doi: 10.1016/j.bmc.2018.02.014. Epub 2018 Feb 13.

Abstract

In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease.

Keywords: Alzheimer’s disease; Butyrylcholinesterase (BuChE); Indoleamine 2,3-dioxygenase 1 (IDO1); Miconazole derivatives; Multifunctional agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Butyrylcholinesterase / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Electrophorus
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Horses
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Ligands
  • Miconazole / chemical synthesis
  • Miconazole / chemistry
  • Miconazole / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • IDO1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Ligands
  • Miconazole
  • Acetylcholinesterase
  • Butyrylcholinesterase