Design, synthesis and evaluation of novel ferulic acid derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease

Abstract A series of new ferulic acid derivatives were designed, synthesized and evaluated as multi-target inhibitors against Alzheimer’s disease. In vitro studies indicated that most compounds showed significant potency to inhibit self-induced β-amyloid (Aβ) aggregation and acetylcholinesterase (AChE), and had good antioxidant activity. Specifically, compound 4g exhibited the potent ability to inhibit cholinesterase (ChE) (IC50, 19.7 nM for hAChE and 0.66 μM for hBuChE) and the good Aβ aggregation inhibition (49.2% at 20 μM), and it was also a good antioxidant (1.26 trolox equivalents). Kinetic and molecular modeling studies showed that compound 4g was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, compound 4g could remarkably increase PC12 cells viability in hydrogen peroxide–induced oxidative cell damage and Aβ-induced cell damage. Finally, compound 4g had good ability to cross the BBB using the PAMPA−BBB assay. These results suggested that compound 4g was a promising multifunctional ChE inhibitor for the further investigation.