Design of a structural framework with potential use to develop balanced multifunctional agents against Alzheimer's disease

A series of small molecules had been designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). The results of biological activity tests showed that most of the molecules exhibited a significant ability to inhibit self-induced beta-amyloid (A beta(1-42)) aggregation, and to function as potential antioxidants and biometal chelators. Among these compounds, compound 3d was found to be highly potent and showed a balanced multifunctional profile covering inhibitory activity against self-induced A beta(1-42) aggregation (IC50 = 7.8 mu M), strong free radical scavenging activities [IC50 (ABTS) = 1.82 mu M; IC50 (DPPH) = 15.4 mu M] and inhibitory activity against MAO-B (IC50 = 6.4 mu M). Moreover, it showed excellent metal chelating properties and good inhibitory activity against Cu2+-induced A beta(1-42) aggregation, and was capable of decreasing reactive oxygen species (ROS) induced by Cu2+-A beta(1-42). Importantly, compound 3d was the most neuroprotective against neuronal death induced by oxidative stress and beta-amyloid (A beta(1-42)), and was able to cross the blood-brain barrier (BBB), according to a parallel artificial membrane permeation assay. These results indicated that compound 3d might be a promising lead compound for AD treatment.