Ferreira João P S, Albuquerque Hélio M T, Cardoso Susana M, Silva Artur M S, Silva Vera L M
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal.
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal.
Eur J Med Chem. 2021 Oct 5;221:113492. doi: 10.1016/j.ejmech.2021.113492. Epub 2021 Apr 24.
Alzheimer's disease (AD) is a chronic neurodegenerative disease and represents the major cause of dementia worldwide. Currently, there are no available treatments capable to deliver disease-modifying effects, and the available drugs can only alleviate the symptoms. The exact pathology of AD is not yet fully understood and several hallmarks such as the presence of amyloid-β (Aβ) senile plaques, neurofibrillary tangles (NFTs) as well as the loss of cholinergic function have been associated to AD. Distinct pharmacological targets have been validated to address AD, with acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) being two of the most explored ones. A great deal of research has been devoted to the development of new AChE and BACE-1 effective inhibitors, tackled separately or in combination of both. The multi-factorial nature of AD conducted to the development of multi-target directed ligands (MTDLs), defined as single molecules capable to modulate more than one biological target, as an alternative approach to the old paradigm one-target one-drug. In this context, this review describes a collection of natural and synthetic compounds with dual-inhibitory properties towards both AChE and BACE-1 in the MTDLs context. Furthermore, this review also provides a critical comprehensive analysis of structure-activity relationships (SAR) of the synthetic compounds.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，也是全球痴呆症的主要病因。目前，尚无能够产生疾病修饰作用的有效治疗方法，现有的药物只能缓解症状。AD的确切病理尚未完全明确，其与一些特征有关，如β淀粉样蛋白（Aβ）老年斑、神经原纤维缠结（NFTs）以及胆碱能功能丧失。已验证了不同的药理学靶点来治疗AD，乙酰胆碱酯酶（AChE）和β-分泌酶-1（BACE-1）是研究最多的两个靶点。大量研究致力于开发新的AChE和BACE-1有效抑制剂，单独或联合进行研究。AD的多因素性质促使了多靶点导向配体（MTDLs）的发展，MTDLs被定义为能够调节多个生物靶点的单一分子，作为对传统单靶点单药物模式的替代方法。在此背景下，本综述描述了在MTDLs背景下对AChE和BACE-1均具有双重抑制特性的天然和合成化合物的集合。此外，本综述还对合成化合物的构效关系（SAR）进行了批判性的综合分析。
