Design, synthesis and biological evaluation of tasiamide B derivatives as BACE1 inhibitors

Bioorg Med Chem. 2015 May 1;23(9):1963-74. doi: 10.1016/j.bmc.2015.03.034. Epub 2015 Mar 20.

Abstract

Nineteen new derivatives based on the structure of marine natural product tasiamide B were designed, synthesized, and evaluated for their inhibitory activity against BACE1, a potential therapeutic target for Alzheimer's disease. The hydrophobic substituents Val at P₃ position, Leu at P₁' position, Ala at P₂' position, and Phe at P₃' position were found to significantly affect the inhibition. Free carboxylic acid at C-terminus was also found to be important to the activity. In addition, the structure-activity relationships (SARs) were supported by molecular docking simulation.

Keywords: Alzheimer’s disease; BACE1 inhibitor; Docking; Synthesis; β-Secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Oligopeptides
  • Protease Inhibitors
  • tasiamide B
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human