Dual inhibitors of butyrylcholinesterase and histone deacetylase 6 for the treatment of Alzheimer’s disease: design, synthesis, and biological evaluation

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-04-30 DOI:10.1016/j.bmc.2025.118219

Bingbing Lv , Zhenqi Wang , Qinjie Wang , Zhaoxin Xu , Jixiong Tang , Yuqiong Pei , Yaoyao Bian , Haopeng Sun , Yao Chen

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Abstract

To address the multifactorial pathology of Alzheimer’s disease (AD), eighteen butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) dual inhibitors were designed, synthesized, and biologically evaluated. Through structure–activity relationship studies, compound 17 emerged as the most potent candidate, with IC₅₀ value of 0.3 nM for human BChE and 56.7 nM for HDAC6. This compound demonstrated favorable safety profiles, drug-like properties, and significant neuroprotective effects in vitro. In a mouse model of scopolamine-induced cognitive impairment, 17 (10 mg/kg) exhibited excellent safety and markedly improved cognitive deficits. These findings highlight compound 17 as a promising BChE/HDAC6 dual inhibitor, supporting its further development as a potential therapeutic agent for AD.

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治疗阿尔茨海默病的丁基胆碱酯酶和组蛋白去乙酰化酶6双重抑制剂：设计、合成和生物学评价

为了解决阿尔茨海默病（AD）的多因素病理，设计、合成了18种丁基胆碱酯酶（BChE）和组蛋白去乙酰化酶6 （HDAC6）双抑制剂，并进行了生物学评价。通过构效关系研究，化合物17对人BChE的IC50值为0.3 nM，对HDAC6的IC50值为56.7 nM，是最有效的候选化合物。该化合物在体外表现出良好的安全性、药物样特性和显著的神经保护作用。在东莨菪碱诱导的认知障碍小鼠模型中，17 （10 mg/kg）表现出极好的安全性，并显著改善认知缺陷。这些发现突出了化合物17作为BChE/HDAC6双抑制剂的前景，支持其作为AD潜在治疗剂的进一步开发。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.