In this study, a series of potential ligands for the treatment of AD were synthesised and characterised as novel harmine derivatives modified at position 9 with benzyl piperazinyl. In vitro studies revealed that the majority of the derivatives exhibited moderate to potent inhibition against hAChE and Abeta(1 - 42) aggregation. Notably, compounds 13 and 17d displayed potent drug - likeness and ADMET properties, demonstrating remarkable inhibitory activities towards AChE (IC(50) = 58.76 nM and 89.38 nM, respectively) as well as Abeta aggregation (IC(50) = 9.31 muM and 13.82 muM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Abeta(1 - 42)-induced SH - SY5Y damage, while maintaining low toxicity in SH - SY5Y cells. Further exploration of the mechanism through kinetic studies and molecular modelling confirmed that compound 13 could interact with both the CAS and the PAS of AChE. These findings suggested that harmine derivatives hold great potential as dual - targeted candidates for treating AD.