Pyridoxine-resveratrol hybrids Mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer's disease

Bioorg Chem. 2017 Apr;71:305-314. doi: 10.1016/j.bioorg.2017.02.016. Epub 2017 Feb 28.

Abstract

A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC50 values of 2.11μM and 1.56μM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC50 value of 2.68μM. The inhibition kinetic analysis revealed that compound 7d showed a mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. Molecular modeling study was also performed to investigate the binding mode of these hybrids with MAO-B. In addition, all target compounds displayed good antioxidant and metal-chelating properties. Taken together, these preliminary findings can be a new starting point for further development of multifunctional agents for Alzheimer's disease.

Keywords: AChE inhibitors; Alzheimer’s disease; Antioxidant; MAO-B inhibitors; Mannich base derivatives; Metal-chelating; Pyridoxine-Resveratrol hybrids.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology
  • Animals
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Electrophorus
  • Humans
  • Kinetics
  • Mannich Bases / chemistry
  • Mannich Bases / pharmacology
  • Metals / metabolism
  • Models, Molecular
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Pyridoxine / analogs & derivatives
  • Pyridoxine / pharmacology*
  • Rats
  • Resveratrol
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*

Substances

  • Antioxidants
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Mannich Bases
  • Metals
  • Monoamine Oxidase Inhibitors
  • Stilbenes
  • Monoamine Oxidase
  • Acetylcholinesterase
  • Pyridoxine
  • Resveratrol