Design, synthesis and preliminary biological evaluation of rivastigmine-INDY hybrids as multitarget ligands against Alzheimer's disease by targeting butyrylcholinesterase and DYRK1A/CLK1 kinases.

ABSTRACT: 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 17 nM respectively. Pleasingly, identification of the matched p

SUBMITTER: Tintas ML 

PROVIDER: S-EPMC10953492 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature