Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors

J Med Chem. 2016 Jan 28;59(2):531-44. doi: 10.1021/acs.jmedchem.5b00894. Epub 2016 Jan 7.

Abstract

The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Blood-Brain Barrier
  • Brain / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Curcumin / chemistry*
  • Curcumin / pharmacology*
  • Drug Design
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • NAD(P)H Dehydrogenase (Quinone) / biosynthesis
  • Neuroprotective Agents / pharmacology
  • Small Molecule Libraries
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Small Molecule Libraries
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Curcumin