Synthesis and Evaluation of Novel Ferulic Amide Derivatives and the Treatment of Alzheimer's Disease

Sixteen ferulic amide (FA) derivatives were designed, synthesized and evaluated as multi-target inhibitors against Alzheimer's disease (AD). In vitro studies indicated that most of the compounds showed significant potency to inhibit acetylcholinesterase (AChE) and self-induced beta-amyloid (A beta) aggregation. Specifically, a dimeric FA analogue with a diamide linker (compound 4 c) exhibited the potent ability to inhibit AChE (IC50, 0.35 mu M) and the good A beta aggregation inhibition (46.6 % at 20 mu M). The structure-activity relationships were also discussed as well as their binding conformation and simultaneous interactions mode were further clarified by the molecular docking studies. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results suggested that compound 4 c was a promising drug candidate against AD.