Design, synthesis and biological evaluation of benzylisoquinoline derivatives as multifunctional agents against Alzheimer's disease

Bioorg Med Chem Lett. 2014 May 15;24(10):2368-73. doi: 10.1016/j.bmcl.2014.03.058. Epub 2014 Apr 3.

Abstract

A novel series of benzylisoquinoline derivatives were designed, synthesized, and evaluated as multifunctional agents against Alzheimer's disease (AD). The screening results showed that most of the compounds significantly inhibited cholinesterases (ChEs), human cholinesterases (h-ChEs) and self-induced β-amyloid (Aβ) aggregation. In particular, compound 9k showed the strongest acetylcholinesterase (AChE) inhibitory activity, being 1000-fold and 3-fold more potent than its precursor benzylisoquinoline (10) and the positive control galanthamine, respectively. In addition, 9k was a moderately potent inhibitor for h-ChEs. Compared with precursor benzylisoquinoline (36.0% at 20μМ), 9k (78.4% at 20μМ) could further inhibit Aβ aggregation. Moreover, 9k showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Therefore, compound 9k might be a promising lead compound for AD treatment.

Keywords: Alzheimer’s disease; Benzylisoquinoline derivatives; Cholinesterase inhibitors; Human cholinesterase inhibitors; Low cell toxicity; β-Amyloid aggregation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Benzylisoquinolines / chemical synthesis*
  • Benzylisoquinolines / chemistry
  • Benzylisoquinolines / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Drug Design
  • Humans
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Benzylisoquinolines
  • Cholinesterase Inhibitors