Chromone derivatives bearing pyridinium moiety as multi-target-directed ligands against Alzheimer's disease.

Abstract A new serise of 7-hydroxy-chromone derivatives bearing pyridine moiety were synthesized, and evaluated as multifunctional agents against Alzheimer’s disease (AD). Most of the compounds were good AChE inhibitors (IC50=9.8-0.71 µM) and showed remarkable BuChE inhibition activity (IC50=1.9-0.006 µM) compared with donepezil as the standard drug (IC50= 0.023 and 3.4 µM). Compounds 14 and 10 showed the best inhibitory activity toward AChE (IC50= 0.71 µM) and BuChE (IC50= 0.006 µM), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 14 and 10 could bind effectively to the peripheral anionic binding site (PAS) of the AChE and BuChE through mixed-type inhibition. In addition, the most potent compounds showed acceptable neuroprotective activity on H2O2- and Aβ-induced .neurotoxicity in PC12 cells, more than standard drugs. The compounds could block effectively self- and AChE-induced Aβ aggregation. All the results suggest that compounds 14 and 10 could be considered as promising multi-target-directed ligands against AD.