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

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 ?M) and showed remarkable BuChE inhibition activity (IC50 = 1.9?0.006 ?M) compared with donepezil as the standard drug (IC50 = 0.023 and 3.4 ?M). Compounds 14 and 10 showed the best inhibitory activity toward AChE (IC50 = 0.71 ?M) and BuChE (IC50 = 0.006 ?M), 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 A?-induced .neurotoxicity in PC12 cells, more than standard drugs. The compounds could block effectively self- and AChE-induced A? aggregation. All the results suggest that compounds 14 and 10 could be considered as promising multi-target-directed ligands against AD.

Automated summary

A new series of 7-hydroxy-chromone derivatives bearing pyridine moiety were synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). Compounds 14 and 10 showed the best inhibitory activity towards AChE and BuChE, with good neuroprotective activity and ability to effectively block A? aggregation.