Profiling donepezil template into multipotent hybrids with antioxidant properties

J Enzyme Inhib Med Chem. 2018 Dec;33(1):583-606. doi: 10.1080/14756366.2018.1443326.

Abstract

Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.

Keywords: Acetylcholinesterase; Alzheimer’s disease; donepezil; multi-target directed ligands; oxidative stress.

Publication types

  • Review

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Donepezil
  • Humans
  • Indans / chemistry
  • Indans / pharmacology*
  • Molecular Structure
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antioxidants
  • Cholinesterase Inhibitors
  • Indans
  • Piperidines
  • Donepezil
  • Acetylcholinesterase

Grants and funding

The work was supported by the grant of Ministry of Health of the Czech Republic [grant No. 15–30954A] by the University of Defense and UHK (Long Term Development Plan), by National Institute of Mental Health (NIMH-CZ) project No. LO1611 with a financial support from the MEYS under the NPU I program.