Multifunctional Analogs of Kynurenic Acid for the Treatment of Alzheimer's Disease: Synthesis, Pharmacology, and Molecular Modeling Studies

ACS Chem Neurosci. 2017 Dec 20;8(12):2667-2675. doi: 10.1021/acschemneuro.7b00229. Epub 2017 Sep 8.


We report the synthesis and pharmacological investigation of analogs of the endogenous molecule kynurenic acid (KYNA) as multifunctional agents for the treatment of Alzheimer's disease (AD). Synthesized KYNA analogs were tested for their N-methyl-d-aspartate (NMDA) receptor binding, mGluR5 binding and function, acetylcholinesterase (AChE) inhibition, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, interference with the amyloid β peptide (Aβ) fibrillation process, and protection against Aβ-induced toxicity in transgenic Caenorhabditis elegans strain GMC101 expressing full-length Aβ42. Molecular modeling studies were also performed to predict the binding modes of most active compounds with NMDAR, mGluR5, and Aβ42. Among the synthesized analogs, 3c, 5b, and 5c emerged as multifunctional compounds that act via multiple anti-AD mechanisms including AChE inhibition, free radical scavenging, NMDA receptor binding, mGluR5 binding, inhibition of Aβ42 fibril formation, and disassembly of preformed Aβ42 fibrils. Interestingly, 5c showed protection against Aβ42-induced toxicity in transgenic C. elegans strain GMC101. Moreover, 5b and 5c displayed high permeability in an MDR1-MDCKII cell-based model of the blood-brain barrier (BBB). Compound 3b emerged with specific activity as a micromolar AChE inhibitor, however it had low permeability in the BBB model. This study highlights the opportunities that exist to develop analogs of endogenous molecules from the kynurenine pathway for therapeutic uses.

Keywords: Alzheimer’s disease; NMDAR antagonist; acetylcholinesterase inhibitor; amyloid β peptide; antioxidant; mGluR5 antagonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Animals
  • Binding Sites
  • Caenorhabditis elegans / anatomy & histology
  • Caenorhabditis elegans / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / chemistry
  • Kynurenic Acid / analogs & derivatives*
  • Kynurenic Acid / chemical synthesis
  • Kynurenic Acid / pharmacology*
  • Models, Chemical
  • Molecular Docking Simulation*
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / chemistry
  • Protein Binding


  • Excitatory Amino Acid Antagonists
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Kynurenic Acid