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  3. Synthesis and evaluation of lipoic acid - donepezil hybrids for Alzheimer's disease using a straightforward strategy

Synthesis and evaluation of lipoic acid - donepezil hybrids for Alzheimer's disease using a straightforward strategy

  • Bioorg Med Chem Lett. 2024 Nov 1:112:129938. doi: 10.1016/j.bmcl.2024.129938.
Vincent Luzet 1,  Florentin Allemand 2,  Chloé Richet 3,  Barbara Dehecq 4,  Alexandre Bonet 5,  Dominique Harakat 6,  Bernard Refouvelet 7,  Hélène Martin 8,  Bruno Cardey 9,  Marc Pudlo 10
Affiliations

Affiliations

  • 1 Université de Franche-Comté, FEMTO-ST, F-25000 Besançon, France. Electronic address: vincent.luzet@femto-st.fr.
  • 2 Université de Franche-Comté, Chrono-environnement UMR6249, CNRS, F-25000 Besançon, France. Electronic address: florentin.allemand@edu.univ-fcomte.fr.
  • 3 Université de Franche-Comté, Chrono-environnement UMR6249, CNRS, F-25000 Besançon, France. Electronic address: chloe.richet@femto-st.fr.
  • 4 Université de Franche-Comté, UMR RIGHT, EFS, INSERM, F-25000 Besançon, France. Electronic address: barbara.dehecq@univ-fcomte.fr.
  • 5 Université de Franche-Comté, UMR RIGHT, EFS, INSERM, F-25000 Besançon, France. Electronic address: alexandre.bonet@univ-fcomte.fr.
  • 6 URCATech, ICMR, CNRS UMR 7312, URCA Bât 18, BP 1039, 51687 Reims Cedex 2, France. Electronic address: dominique.harakat@univ-reims.fr.
  • 7 Université de Franche-Comté, UMR INSERM 1322 LINC, F-25030 Besançon Cedex, France. Electronic address: bernard.refouvelet@univ-fcomte.fr.
  • 8 Université de Franche-Comté, UMR RIGHT, EFS, INSERM, F-25000 Besançon, France. Electronic address: helene.martin@univ-fcomte.fr.
  • 9 Université de Franche-Comté, Chrono-environnement UMR6249, CNRS, F-25000 Besançon, France. Electronic address: bruno.cardey@univ-fcomte.fr.
  • 10 Université de Franche-Comté, UMR RIGHT, EFS, INSERM, F-25000 Besançon, France. Electronic address: marc.pudlo@univ-fcomte.fr.
PMID: 39222891 DOI: 10.1016/j.bmcl.2024.129938
Abstract

Alzheimer's disease is associated with a progressive loss of neurons and synaptic connections in the cholinergic system. Oxidative stress contributes to neuronal damages and to the development of amyloid plaques and neurofibrillary tangles. Therefore, Antioxidants have been widely studied to mitigate the progression of Alzheimer's disease, and among these, lipoic acid has demonstrated a neuroprotective effect. Here, we present the synthesis, the molecular modelling, and the evaluation of lipoic acid-donepezil hybrids based on O-desmethyldonepezil. As compounds 5 and 6 display a high inhibition of acetylcholinesterase (IC50 = 7.6 nM and 9.1 nM, respectively), selective against butyrylcholinesterase, and a notable neuroprotective effect, slightly better than that of lipoic acid, the present study suggests that O-desmethyldonepezil could serve as a platform for the straightforward design of donepezil hybrids.

Keywords

Acetylcholinesterase; Alzheimer disease; Antioxidant; Donepezil; Lipoic acid; Neuroprotection.

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