Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease

ChemMedChem. 2016 Jun 20;11(12):1264-9. doi: 10.1002/cmdc.201500383. Epub 2015 Oct 2.

Abstract

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 μm), butyrylcholinesterase (BChE IC50 : 2.4 μm) and MAO A (IC50 : 0.49 μm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 μm). Although its cytotoxic (IC50 : 5.5±0.4 μm) and hepatotoxic (IC50 : 1.22±0.11 μm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77 μm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.

Keywords: Alzheimer's disease; cholinesterases; cytotoxicity; inhibitors; monoamine oxidase; multitarget-directed ligands.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Blood-Brain Barrier / metabolism
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / therapeutic use*
  • Cholinesterase Inhibitors / toxicity
  • Drug Design*
  • Hep G2 Cells
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / therapeutic use
  • Indoles / toxicity
  • Inhibitory Concentration 50
  • Ligands
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / metabolism
  • Monoamine Oxidase Inhibitors / therapeutic use*
  • Monoamine Oxidase Inhibitors / toxicity
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Quinolines / therapeutic use
  • Quinolines / toxicity
  • Structure-Activity Relationship
  • Tacrine / chemistry*
  • Tacrine / metabolism
  • Tacrine / therapeutic use
  • Tacrine / toxicity

Substances

  • 9-methoxy-2,3,4,6-tetrahydro-1H-indolo(2,3-b)quinolin-11-amine
  • Cholinesterase Inhibitors
  • Indoles
  • Ligands
  • Monoamine Oxidase Inhibitors
  • Quinolines
  • indolo(2,3-b)quinoline
  • Tacrine
  • Monoamine Oxidase
  • Acetylcholinesterase