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.

伴随丁酰胆碱酯酶（BChE）和组蛋白脱乙酰化酶6（HDAC6）的抑制，据信对治疗阿尔茨海默病（AD）具有显著效果。受先前设计BChE抑制剂努力的启发，本研究中，通过融合BChE和HDAC6抑制剂的核心药效基团，成功识别了选择性的BChE/HDAC6双重抑制剂。在结构-活性关系（SAR）研究之后，确认了两种化合物（24g和29a）对BChE具有优异的抑制作用（对hBChE的IC50分别为4.0和1.8 nM），对HDAC6亦然（对HDAC6的IC50分别为8.9和71.0 nM）。这两种化合物在体外显示出显著的神经保护作用、强大的活性氧（ROS）清除效果以及有效的金属离子（Fe2+和Cu2+）螯合作用。此外，它们对磷酸化tau蛋白表现出显著的抑制作用，并具有一定的免疫调节作用，在细胞水平上无神经毒性。体内研究表明，24g和29a在低剂量（2.5 mg/kg）下可改善由Aβ1–42诱导的小鼠模型中的认知障碍。我们的数据表明，BChE/HDAC6双重抑制剂有望为治疗AD的潜在新症状缓解及疾病修饰策略奠定基础。