Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor

Abstract : Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (±)-cis-1, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of 1 by HPLC and (ii) preparing two close achiral analogues of 1, i.e., compounds 4 and 6. An eudismic ratio as high as 20 was observed for the (-) enantiomer of cis-1. The X-ray crystal structure of the complex between the (-)-cis-1 eutomer (coded as MC1420) and T. californica AChE was determined at 2.8 Å, and docking calculation results suggested that the eutomer in (1R,3S) absolute configuration should be energetically more favored in binding the enzyme than the eutomer in (1S,3R) configuration. The achiral analogues 4 and 6 were less effective in inhibiting AChE compared to (±)-cis-1, but interestingly butylamide 4 emerged as a potent inhibitor of butyrylcholinesterase (BChE).
Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal.univ-grenoble-alpes.fr/hal-02864326
Contributeur : Frank Thomas <>
Soumis le : jeudi 11 juin 2020 - 08:42:28
Dernière modification le : mercredi 22 juillet 2020 - 03:13:41

Identifiants

Collections

Citation

Marco Catto, Leonardo Pisani, Eugenio de la Mora, Benny Danilo Belviso, Giuseppe Felice Mangiatordi, et al.. Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor. ACS Medicinal Chemistry Letters, American Chemical Society, 2020, 11 (5), pp.869-876. ⟨10.1021/acsmedchemlett.9b00656⟩. ⟨hal-02864326⟩

Partager

Métriques

Consultations de la notice

38