Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
Himachal Pradesh Technical University, Hamirpur, Himachal Pradesh, India.
Chem Biol Drug Des. 2024 Oct;104(5):e70004. doi: 10.1111/cbdd.70004.
Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aβ) in the form of Aβ plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-β (Aβ) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.
阿尔茨海默病（AD）是一种进行性慢性与年龄相关的神经退行性脑疾病，其特征是记忆和其他认知功能丧失。AD的确切病因仍在研究中，然而，一些因素，如神经递质乙酰胆碱（ACh）水平低、β淀粉样蛋白（Aβ）以 Aβ斑块的形式聚集、tau 蛋白过度磷酸化为神经原纤维缠结（NFTs）、氧化应激和金属离子失衡，是这种疾病的主要特征。在 AD 的多种假说中，淀粉样蛋白-β（Aβ）和胆碱能假说是 AD 的主要靶向假说。一些研究人员假设，与胆碱能神经递质（乙酰胆碱）相关的主要事件是记忆丧失和认知障碍。由于疾病的发病机制复杂，长期使用单一靶点候选药物是无效的。因此，出现了多靶点和多功能疗法。各种研究团队都专注于通过杂交技术解决多种疾病因素。因此，这种杂交方法已应用于所有核心支架，包括加兰他敏。在本文中，我们试图全面概述加兰他敏作为一种有前途的乙酰胆碱酯酶抑制剂及其作为治疗 AD 的潜在治疗剂的混合类似物的最新进展。此外，我们还提供了过去几十年用于 AD 管理的基于加兰他敏的化合物的设计、合成和 SAR 分析。
