Design, synthesis, and in vitro evaluation of 4-aminoalkyl-1(2H)-phthalazinones as potential multifunctional anti-Alzheimer's disease agents

Bioorg Chem. 2021 Jun:111:104895. doi: 10.1016/j.bioorg.2021.104895. Epub 2021 Apr 8.

Abstract

A series of 4-aminoalkyl-1(2H)-phthalazinone derivatives was designed and synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. In vitro biological assay results demonstrated that most synthesized compounds exhibited significant AChE inhibition, moderate to high MAOs inhibitory potencies and good anti-platelet aggregation abilities. Among them, compound 15b exhibited the highest inhibitory potencies towards MAO-B and MAO-A (IC50 = 0.7 µM and 6.4 µM respectively), moderate inhibition towards AChE (IC50 = 8.2 µM), and good activities against self- and Cu2+-induced Aβ1-42 aggregation and platelet aggregation. Moreover, 15b also displayed antioxidant capacity, neuroprotective potency, anti-neuroinflammation and BBB permeability. These excellent results indicated that compound 15b could be worthy of further studies to be considered as a promising multifunctional candidate for the treatment of AD.

Keywords: 4-(aminoalkyl)-1(2H)-phthalazinone derivatives; Acetylcholinesterase inhibitors; Alzheimer’s disease; Anti-neuroinflammation; Aβ aggregation inhibitors; Monoamine oxidases inhibitors; Multifunctional agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Electrophorus
  • Humans
  • Molecular Structure
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Phthalazines / chemical synthesis
  • Phthalazines / chemistry
  • Phthalazines / pharmacology*
  • Platelet Aggregation / drug effects
  • Protein Aggregates / drug effects
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Monoamine Oxidase Inhibitors
  • Neuroprotective Agents
  • Peptide Fragments
  • Phthalazines
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • Monoamine Oxidase
  • monoamine oxidase A, human
  • Acetylcholinesterase
  • Butyrylcholinesterase