Design, synthesis and biological evaluation of novel chiral oxazino-indoles as potential and selective neuroprotective agents against Aβ25-35-induced neuronal damage

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3765-9. doi: 10.1016/j.bmcl.2016.05.061. Epub 2016 Jun 3.

Abstract

A series of chiral oxazino-indoles have been synthesized via a key intermolecular oxa-Pictet-Spengler reaction. These compounds exhibited significant and selective neuroprotective effects against Aβ25-35-induced neuronal damage. This is the first report of evaluating the influence of chiral diversity of oxazino-indoles on their neuroprotective activities, with the structure-activity relationship been analyzed. The highly active compounds 3f, 3g, 4g, 4h, and 6b all performed over 90% cell protection, providing a new direction for the development of neuroprotective agents against Alzheimer's disease.

Keywords: Alzheimer’s disease; Neuroprotective agent; Oxa-Pictet–Spengler reaction; Oxazino-indoles; SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Oxazines / chemistry
  • Oxazines / pharmacology*
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Indoles
  • Neuroprotective Agents
  • Oxazines
  • Peptide Fragments
  • amyloid beta-protein (25-35)