Enzymatic and solid-phase synthesis of new donepezil-based L-and D-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer ' s disease and cerebral ischemia

Leticia Monjas, Mariana P. Arce, Rafael Leon, Javier Egea, Concepcion Perez, Mercedes Villarroya, Manuela G. Lopez, Carmen Gil, Santiago Conde, Maria Isabel Rodriguez-Franco*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

Abstract

Previously, we have described N-Bz-L-Glu[ NH-2-(1-benzylpiperidin-4-yl) ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L-and D-Glu diesters with N-benzyl-4-(2-aminoethyl) piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the alpha-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L-and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[ NH-2-(1benzylpiperidin-4-yl) ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising antiAlzheimer and anti-stroke lead compounds. (C) 2017 Elsevier Masson SAS. All rights reserved.

Original languageEnglish
Pages (from-to)60-72
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume130
DOIs
Publication statusPublished - 21-Apr-2017

Keywords

  • Donepezil-based L and D-Glu derivatives
  • Human cholinesterases
  • Neuroprotection
  • Mitochondrial oxidative stress
  • Alzheimer ' s disease
  • Stroke
  • LIPASE-CATALYZED SYNTHESIS
  • ACETYLCHOLINESTERASE INHIBITORS
  • OXIDATIVE STRESS
  • NEUROPROTECTIVE PROPERTIES
  • MULTIFUNCTIONAL AGENTS
  • COMPOUND ITH33/IQM9.21
  • N-BENZYLPIPERIDINE
  • IN-VITRO
  • MULTITARGET
  • HYBRIDS

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