Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer's disease therapy

J Enzyme Inhib Med Chem. 2019 Dec;34(1):163-170. doi: 10.1080/14756366.2018.1538136.


In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.

Keywords: Alzheimer disease; kojic acid; multitarget small molecules; tacrine.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Structure-Activity Relationship
  • Tacrine / chemical synthesis
  • Tacrine / chemistry
  • Tacrine / pharmacology*


  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Tacrine
  • Acetylcholinesterase

Grants and funding

LI thanks the Regional Council of Franche-Comte (2016YC-04540 and 04560) for financial support. OS thanks Faculty of Military Health Sciences, University of Defense, MH CZ – DRO (UHHK, 00179906) and by Long Term Development Plan – 1011 for support. JMC thank MINECO (Spain) for grant SAF2012-33304 and EU (COST Action CA15135: “Multi-target paradigm for innovative ligand identification in the drug discovery process”) for support.