Interest of novel N-alkylpyridinium-indolizine hybrids in the field of Alzheimer's disease: synthesis, characterization and evaluation of antioxidant activity, cholinesterase inhibition, and amyloid fibrillation interference - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Bioorganic Chemistry Année : 2021

Interest of novel N-alkylpyridinium-indolizine hybrids in the field of Alzheimer's disease: synthesis, characterization and evaluation of antioxidant activity, cholinesterase inhibition, and amyloid fibrillation interference

Résumé

A small library of molecules combining indolizine and N-alkyl pyridinium was synthesized and evaluated in a multi-target-directed-ligand strategy for Alzheimer's disease (AD) treatment. The new compounds were classified in three series depending on the number of methylene residues linking the two heterocycles (Ind-PyCx with x = 0, 2 or 3). The molecules were synthesized from the corresponding bis-pyridines by two-step formation of the indolizine core including mono-alkylation of pyridine and 1,3-dipolar cycloaddition with an alkylpropiolate. Their activities against AD's key-targets were evaluated in vitro: acetyl-and butyrylcholinesterase (AChE and BChE) inhibition, antioxidant properties and inhibition of amyloid fibril formation (ThT assays). None of the three series showed significant activities against all the targets. The Ind-PyC2 and Ind-PyC3 series are relatively active on eeAChE and hAChE (µM IC50 values). Except compound 10 and 15, charged molecules appeared also active against eqBChE with micromolar IC50, while they lost their activity on hBChE. Comparative molecular modeling of 13 and 15 docked in hAChE and hBChE highlighted the importance of the substituent pmethoxybenzoyl or methyloxycarbonyl located on the indolizine part for the binding. The molecules displayed antioxidant activity at the highest tested concentration, up to 95% inhibition of DPPH radical scavenging for 10. Most of the Ind-PyC2 and Ind-PyC3 hybrids were able also to interact with amyloid fibers even if the observed inhibitory effect on fibrillation process was observed at a high 100 µM concentration. For the Ind-PyC0 series, despite the fact that their spectroscopic properties did not allow their evaluation with ThT assay, they showed interesting features in the presence of preformed fibers. In particular, the sharp increase of the fluorescence of 3 in the presence of amyloid fibers is a promising indication of the potential use of this series as fluorescent amyloid fibrillation reporter.
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Dates et versions

hal-03365026 , version 2 (06-10-2021)
hal-03365026 , version 1 (19-11-2021)
hal-03365026 , version 3 (19-11-2021)

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  • HAL Id : hal-03365026 , version 1

Citer

Isabelle Baussanne, Olga Firstova, Andreea Botezatu Dediu, Camille Larosa, Bianca Furdui, et al.. Interest of novel N-alkylpyridinium-indolizine hybrids in the field of Alzheimer's disease: synthesis, characterization and evaluation of antioxidant activity, cholinesterase inhibition, and amyloid fibrillation interference. Bioorganic Chemistry, 2021. ⟨hal-03365026v1⟩
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