Design, Synthesis and Preliminary Biological Evaluation of Rivastigmine-INDY Hybrids as Multitarget Ligands Against Alzheimer's Disease by Targeting Butyrylcholinesterase and DYRK1A/CLK1 Kinases - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue RSC Medicinal Chemistry Année : 2024

Design, Synthesis and Preliminary Biological Evaluation of Rivastigmine-INDY Hybrids as Multitarget Ligands Against Alzheimer's Disease by Targeting Butyrylcholinesterase and DYRK1A/CLK1 Kinases

Résumé

Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of eqBuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with hDYRK1A/hCLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the N-appendage of the benzothiazole core led to potent and selective eqBuChE inhibitors with IC50 up to 27 nM and potent hDYRK1A and hCLK1 inhibitors with IC50 up to 106 nM and 17nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of eqBuChE and hDYRK1A/hCLK1 kinases (IC50 = 68 nM and IC50 = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound 1b exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate.
Fichier sous embargo
Fichier sous embargo
0 3 20
Année Mois Jours
Avant la publication
mardi 20 août 2024
Fichier sous embargo
mardi 20 août 2024
Connectez-vous pour demander l'accès au fichier

Dates et versions

hal-04478385 , version 1 (26-02-2024)

Identifiants

Citer

Mihaela-Liliana Tintas, Ludovic Peauger, Anaïs Barré, Cyril Papamicael, Thierry Besson, et al.. Design, Synthesis and Preliminary Biological Evaluation of Rivastigmine-INDY Hybrids as Multitarget Ligands Against Alzheimer's Disease by Targeting Butyrylcholinesterase and DYRK1A/CLK1 Kinases. RSC Medicinal Chemistry, In press, ⟨10.1039/D3MD00708A⟩. ⟨hal-04478385⟩
16 Consultations
2 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More