The Evolution of AChE Inhibitors in Alzheimer's Disease: From Single-Target to Multi-Target Ligands

IF 2.8 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

ChemBioChem Pub Date : 2025-07-28 DOI:10.1002/cbic.202500053

Namrashee V. Mehta, Akshay Kapadia, Mihir Khambete, Arundhati Abhyankar

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Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disease marked by cognitive decline, neuronal degeneration, and the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. Current treatment strategies, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor antagonists, offer symptomatic relief but fail to stop disease progression. The development of multi-target-directed ligands (MTDLs) has gained attention as a method to address the complex pathology of AD. This review provides a detailed account of the journey of AChE inhibitors from single-target ligands to MTDLs, emphasizing the structural changes that improve target specificity, blood–brain barrier penetration, and therapeutic impact. By exploring these advancements, the review highlights the potential of MTDLs to overcome the limitations of traditional single-target approaches and contribute to the discovery of more effective anti-Alzheimer therapies along with discussing potential pitfalls.

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阿尔茨海默病中AChE抑制剂的进化：从单靶点到多靶点配体

阿尔茨海默病（AD）是一种慢性神经退行性疾病，其特征是认知能力下降、神经元变性、细胞内神经原纤维缠结、细胞外淀粉样斑块和神经炎症的积累。目前的治疗策略，如乙酰胆碱酯酶抑制剂（AChEIs）和n -甲基- d -天冬氨酸受体拮抗剂，提供症状缓解，但不能阻止疾病进展。多靶标定向配体（mtdl）的发展作为一种解决AD复杂病理的方法受到了关注。本文详细介绍了乙酰胆碱酯酶抑制剂从单靶点配体到mtdl的发展历程，强调了其结构变化可提高靶点特异性、血脑屏障穿透性和治疗效果。通过探索这些进展，本综述强调了mtdl克服传统单靶点方法局限性的潜力，并有助于发现更有效的抗阿尔茨海默病治疗方法，同时讨论了潜在的缺陷。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemBioChem 生物-生化与分子生物学

CiteScore

6.10

自引率

3.10%

发文量

407

审稿时长

1 months

期刊介绍： ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).