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
(24g and 29a) were confirmed to have superior
inhibitory activity against BChE (the IC50 against hBChE are 4.0 and 1.8 nM, respectively) and HDAC6 (the IC50 against HDAC6 are 8.9 and 71.0 nM, respectively). These
two compounds showed prominently neuroprotective effects in
vitro, potent reactive oxygen species (ROS) scavenging effects,
and effective metal ion (Fe2+ and Cu2+) chelation.
In addition, they exhibited pronounced inhibition of phosphorylated
tau and a moderate immunomodulatory effect, with a lack of neurotoxicity
at the cellular level. In vivo studies showed that
both 24g and 29a ameliorated the cognitive
impairment in an Aβ1–42-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.