Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer's disease

The abnormal phosphorylation of the tau-protein is a typical early pathological feature of Alzheimer's disease (AD). The excessive phosphorylation of the tau-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-beta (A beta). Thus, targeting the tau-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the tau-protein and the E3 ligase. The molecules were examined in vitro, and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound 13 in healthy rats. Our data showed that compound 13 could effectively degrade tau-protein, reduce A beta-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD.