| Title: |
Design, Synthesis and Preliminary Biological Evaluation of Rivastigmine-INDY Hybrids as Multitarget Ligands Against Alzheimer's Disease by Targeting Butyrylcholinesterase and DYRK1A/CLK1 Kinases |
| Authors: |
Tintas, Mihaela-Liliana; Peauger, Ludovic; Barré, Anaïs; Papamicael, Cyril; Besson, Thierry; Sopkova de Oliveira Santos, Jana; Gembus, Vincent; Levacher, Vincent |
| Contributors: |
Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA); Institut de Chimie Organique Fine (IRCOF); Université de Rouen Normandie (UNIROUEN); Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie); Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN); Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M); Université de Caen Normandie (UNICAEN); Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN); Normandie Université (NU)-Université Le Havre Normandie (ULH); Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN); Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie); Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN); Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN); Normandie Université (NU)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS); Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN); Normandie Université (NU)-Normandie Université (NU) |
| Source: |
ISSN: 2632-8682 ; RSC Medicinal Chemistry ; https://hal.science/hal-04478385 ; RSC Medicinal Chemistry, In press, ⟨10.1039/D3MD00708A⟩. |
| Publisher Information: |
CCSD; Royal Society of Chemistry |
| Publication Year: |
2024 |
| Collection: |
Normandie Université: HAL |
| Subject Terms: |
[CHIM.THER]Chemical Sciences/Medicinal Chemistry; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1039/D3MD00708A |
| Availability: |
https://hal.science/hal-04478385; https://hal.science/hal-04478385v1/document; https://hal.science/hal-04478385v1/file/RSC%20Chem%20Med-Accepted%20Manuscript.pdf; https://doi.org/10.1039/D3MD00708A |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.12D79A60 |
| Database: |
BASE |