Liu_2022_Eur.J.Med.Chem_242_114689

Multi-targeted directed ligands (MTDLs) are emerging as promising Alzheimer's disease (AD) therapeutic possibilities. Coumarin is a multifunctional backbone with extensive bioactivity that has been utilized to develop innovative anti-neurodegenerative properties and is a desirable starting point for the construction of MTDLs. Herein, we explored and synthesized a series of novel coumarin derivatives and assessed their inhibitory effects on cholinesterase (AChE, BuChE), GSK-3beta, and BACE1. Among these compounds, compound 30 displayed the multifunctional profile of targeting the AChE (IC(50) = 1.313 +/- 0.099 microM) with a good selectivity over BuChE (SI = 24.623), GSK-3beta (19.30% inhibition at 20 microM), BACE1 (IC(50) = 1.227 +/- 0.112 microM), along with moderate HepG2 cytotoxicity, SH-SY5Y cytotoxicity, low HL-7702 cytotoxicity, as well as good blood-brain barrier (BBB) permeability. Kinetic and docking studies indicated that compound 30 was a competitive AChE inhibitor. Furthermore, acute toxicity experiments revealed that it was non-toxic at a dosage of 1000 mg/kg. The ADME prediction results indicate that 30 has acceptable physicochemical properties. Collectively, these findings demonstrated that compound 30 would be a potential multifunctional candidate for AD therapy.