Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors

A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC₅₀ value of 8.9 nM and high AChE/BuChE selectivity (SI >230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.