(±)-: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease.

Fiche publication

Date publication

avril 2021

Journal

ACS chemical neuroscience

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BAGUET Aurélie , Pr HAFFEN Emmanuel

Tous les auteurs :
Ismaili L, Monnin J, Etievant A, Arribas RL, Viejo L, Refouvelet B, Soukup O, Janockova J, Hepnarova V, Korabecny J, Kucera T, Jun D, Andrys R, Musilek K, Baguet A, García-Frutos EM, De Simone A, Andrisano V, Bartolini M, de Los Ríos C, Marco-Contelles J, Haffen E

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33797877

Résumé

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±) was identified as a promising new hit compound showing balanced activities toward the aforementioned recognized AD targets. Additional studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The studies have shown that (±) (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.