New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer's disease

Eur J Med Chem. 2015 Oct 20:103:302-11. doi: 10.1016/j.ejmech.2015.08.052. Epub 2015 Sep 5.

Abstract

A novel series of melatonin-derived benzylpyridinium bromides have been designed, synthesized, and evaluated as multi-functional anti-AD agents with cholinesterase inhibitory, antioxidant, and neuroprotective activities. In vitro studies showed that most of these compounds exhibited potent inhibitory activity toward h-AChE and h-BuChE, and good antioxidant capacity in the ORAC assay. In particular, compound 19 was the most attractive derivative, showing the highest potency to inhibit ChEs (AChE: IC₅₀ = 0.11 μM; BuChE: IC₅₀ = 1.1 μM) and good antioxidant ability (ORAC (trolox) = 3.41). Kinetic and molecular modeling studies indicated that 19 was a mixed-type inhibitor, binding simultaneously to active and peripheral sites of AChE. Moreover, 19 also showed good neuroprotective effects in human SH-SY5Y neuroblastoma cells. Taken together, these results suggested that compound 19 might be a promising multi-target drug candidate worthy of further pursuit.

Keywords: Alzheimer's disease; Antioxidant; Benzylpyridinium; Cholinesterase; Melatonin; Neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Melatonin / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Pyridinium Compounds / chemical synthesis
  • Pyridinium Compounds / chemistry*
  • Pyridinium Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • 1-(3-fluorobenzyl)-4-(3-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-3-oxoprop-1-en-1-yl)pyridin-1-ium
  • Antioxidants
  • Cholinesterase Inhibitors
  • Indoles
  • Neuroprotective Agents
  • Pyridinium Compounds
  • Cholinesterases
  • Melatonin