Normandie Univ, UNICAEN, CERMN, 14000 Caen, France.
Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, 70125 Bari, Italy.
Molecules. 2020 Dec 27;26(1):80. doi: 10.3390/molecules26010080.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic PADPZ was achieved and its biological evaluation established its inhibitory activities towards both ()AChE (IC = 0.4 µM) and ()MAO-B (IC = 6.4 µM).
阿尔茨海默病（AD）是一种多因素神经退行性疾病，目前人们认为使用多靶点定向配体的多效方法可能是方便的。在当今针对 AD 验证的众多靶点中，乙酰胆碱酯酶（AChE）和单胺氧化酶-B（MAO-B）似乎特别有说服力，特别是如果由拉多替吉（ladostigil）等单一药物显示出来，目前正在 AD 中进行临床试验。考虑到这些结果，我们希望利用他唑司坦（donepezil，DPZ）和雷沙吉兰（rasagiline）之间存在的结构相似性，这两种茚满衍生物分别作为 AChE 和 MAO-B 抑制剂上市，并提出这两种化合物之间的结构折衷的合成和初步体外生物学特性研究，我们称之为炔丙基氨基多奈哌齐（propargylaminodonepezil，PADPZ）。对映体 PADPZ 的合成已完成，其生物学评价确定了其对（）乙酰胆碱酯酶（IC = 0.4 µM）和（）MAO-B（IC = 6.4 µM）的抑制活性。
