Design, Synthesis, and Proof of Concept of Balanced Dual Inhibitors of Butyrylcholinesterase (BChE) and Histone Deacetylase 6 (HDAC6) for the Treatment of Alzheimer's Disease.

Concomitant inhibition of butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) is supposed to be effective in the treatment of Alzheimer's disease (AD). Inspired by our previous efforts in designing BChE inhibitors, herein, selective BChE and HDAC6 dual inhibitors were successfully identified through the fusion of the core pharmacophoric moiety of BChE and HDAC6 inhibitors. After the structure-activity relationship (SAR) studies, two compounds ( and ) were confirmed to have superior inhibitory activity against BChE (the IC against BChE are 4.0 and 1.8 nM, respectively) and HDAC6 (the IC against HDAC6 are 8.9 and 71.0 nM, respectively). These two compounds showed prominently neuroprotective effects , potent reactive oxygen species (ROS) scavenging effects, and effective metal ion (Fe and Cu) chelation. In addition, they exhibited pronounced inhibition of phosphorylated tau and a moderate immunomodulatory effect, with a lack of neurotoxicity at the cellular level. studies showed that both and ameliorated the cognitive impairment in an Aβ-induced mouse model at a low dosage (2.5 mg/kg). Our data demonstrated that BChE/HDAC6 dual inhibitors could establish the basis for a potential new symptomatic and disease-modifying strategy to treat AD.