深入了解治疗阿尔茨海默病的胆碱酯酶和 BACE-1 抑制剂的药物化学和 SAR 研究。

Abhimannu Shome, Keshav Taruneshwar Jha, Chahat, Viney Chawla, Pooja A Chawla
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摘要

阿尔茨海默病(AD)是一种严重的神经退行性疾病,主要影响内叶皮层和海马区的胆碱能神经元,这些神经元在学习、导航和大脑处理过程中发挥着关键作用。本文旨在讨论阿尔茨海默病的三个主要假说,重点是线粒体功能障碍和 ROS 生成导致的神经毒性和神经变性,尤其是分析两性之间的易感性差异。我们的综合综述重点关注过去五年的重大发现,尤其是胆碱酯酶(ChE)和 BACE-1 抑制剂。研究人员对体外、硅学和体内数据进行了详细分析,并进行了广泛的结构-活性关系(SAR)研究。综述论文来自 Google Scholar、Semantic Scholar 和 ClinicalTrials.gov 等平台,根据其 AChE 和 BACE-1 抑制活性和结构相似性进行筛选。综述确定了针对胆碱酯酶和 BACE-1 的最有效化合物,重点介绍了抑制胆碱酯酶的吖啶、二氢吡啶和噻唑-香豆素杂交化合物,以及抑制 BACE-1 的噁二唑、苯并呋喃和二氢嘧啶酮。这展示了多种多样的强效杂环化合物。本综述汇集了各种有望治疗阿尔茨海默病的支架,突出了特定化合物对 ChE 和 BACE-1 的潜在作用。考虑到我们的分析所得出的重要见解,我们认为这篇综述将极大地推动目前对抗神经变性和延长痴呆症的工作,并强调了在这一领域持续开展研究的重要性。
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An Insight into Medicinal Chemistry and SAR Studies of Cholinesterase and BACE-1 Inhibitors for Alzheimer's Disease.

Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors. Researchers have conducted a detailed analysis of in vitro, in silico, and in vivo data, incorporating extensive Structure-Activity Relationship (SAR) studies. The reviewed papers have been sourced from platforms, such as Google Scholar, Semantic Scholar, and ClinicalTrials.gov, and have been selected based on their AChE and BACE-1 inhibitory activity and structural motif similarity. The review identifies the most effective compounds targeting ChE and BACE-1, highlighting acridine, dihydropyridine, and thiazole-coumarin hybrids for ChE inhibition, and oxadiazole, benzofuran, and dihydropyrimidinone for BACE-1 inhibition. This demonstrates a diverse array of potent heterocyclic hybrids. The review presents a varied compilation of scaffolds showing promise in treating Alzheimer's disease, highlighting the potential of specific compounds against ChE and BACE-1. Given the critical insights derived from our analysis, we posit that this compilation will substantially contribute to the ongoing efforts to combat neurodegeneration and prolong dementia, underscoring the importance of continuous research in this domain.

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