Abd_2024_Bioorg.Chem_154_108024

The traditional theory of "one drug, one target, one illness" has come under scrutiny owing to the multifactorial nature of Alzheimer's disease (AD) and the failure of most of its medications, therefore multi-target directed ligands (MTDLs) are prospective therapeutics for AD. In the present study, we synthesized novel series of coumarin derivatives and assessed their inhibitory actions against hAChE, hBuChE, GSK-3beta, tau protein and Abeta aggregation. Compounds 6c and 6h stood out among the others with their multifunctional profile. With IC(50) values of 28.88 and 26.03 nM, respectively, compounds 6c and 6h showed outstanding activity as hAChE inhibitors and demonstrated good inhibitory activity against hBuChE with IC(50) values of 103.90 and 90.09 nM along with appropriate action against GSK-3beta in nanomolar range. Also, both compounds 6c and 6h were found to outperform the reported anti-AD donepezil as tau protein aggregation and amyloid aggregation (Abeta) inhibitors as well as low cytotoxicity on healthy neuroblastoma SHSY5Y and hepatic THLE2 cells. Kinetic analysis and docking studies indicated hAChE dual site (mixed) inhibitory effect of compound 6h. Both compounds 6c and 6h complied with Lipinski's rule of five and were virtually able to cross the BBB. All the data suggested that compounds 6c and 6h have potential as a multifunctional therapy for AD.