Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab-142001,India.
Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP,India.
Curr Alzheimer Res. 2021;18(10):802-830. doi: 10.2174/1567205018666211208140551.
Alzheimer's disease (AZD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cognitive domains, including executive function. The progression of AZD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AZD include a decreased concentration of acetylcholine (ACh), deposition of amyloid-β (Aβ) peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AZD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid molecules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffold have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-Aβ aggregation. In the present review, we have focused on different reported coumarin hybrids as multi-target-directed agents against AZD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hydroxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hybrids, important clinical investigations and the structure-activity relationship have also been discussed in this compilation.
阿尔茨海默病（AZD）是一种与年龄相关的神经退行性疾病，也是全球常见的健康问题之一。其特征是记忆力减退和其他认知领域（包括执行功能）的下降。AZD 的进展与复杂事件有关，确切的发病机制仍未揭示。各种被认为与 AZD 发病有关的机制包括乙酰胆碱（ACh）浓度降低、淀粉样β（Aβ）肽沉积、氧化还原金属离子的动态平衡失调以及氧化应激延长。由于多种发病途径的同时进展，迄今为止尚未开发出理想的治疗剂。目前用于治疗 AZD 的药物仅提供对症益处，没有疾病修饰活性。因此，为了寻找理想的治疗候选物，近年来人们一直在深入研究分子杂合体的概念。杂合体能够同时抑制、激活或修饰一个以上的靶标生理机能。香豆素骨架已显示出对 ACh 酯酶抑制、MAO-B 抑制和抗 Aβ 聚集的优异潜力。在本综述中，我们重点介绍了不同报道的作为多靶点定向剂的香豆素杂合体。这些包括香豆素与咔唑、苯并呋喃、二硫代氨基甲酸盐、喹啉、帕吉林、他克林、N-苄基吡啶鎓、多奈哌齐、嘌呤、哌啶、吗啉、氨基酚、苄基氨基、卤代苯烷基酰胺、噻唑、硫脲、羟基吡啶酮、三唑、哌嗪、查耳酮等的杂合体。除了这些杂合体的治疗潜力外，本综述还讨论了重要的临床研究和构效关系。
