Phthalimide-(N-alkylbenzylamine) cysteamide hybrids as multifunctional agents against Alzheimer's disease: Design, synthesis, and biological evaluation.

The complex pathogenesis of Alzheimer's disease (AD) calls for multi-target approach for disease treatment. Herein, based on the MTDLs strategy, a series of phthalimide-(N-alkylbenzylamine) cysteamide hybrids were designed, synthesized, and investigated in vitro for the purpose. Most of the target compounds were found to be potential multi-target agents. In vitro results showed that compound 9e was the representative compound in this series, endowed with high EeAChE and HuAChE inhibitory potency (IC50  = 1.55 µm and 2.23 µm, respectively), good inhibitory activity against self-induced Aβ1-42 aggregation (36.08% at 25 µm), and moderate antioxidant capacity (ORAC-FL value was 0.68 Trolox equivalents). Molecular docking studies rationalized the binding mode of 9e in both PAS and CAS of AChE. Moreover, 9e displayed excellent ability to against H2 O2 -induced PC12 cell injury and penetrate BBB. Overall, these results highlighted that compound 9e was an effective and promising multi-target agent for further anti-AD drug development.