Department of Pharmacology, School of Pharmaceutical Education and Research, JamiaHamdard, New Delhi-110062, India.
Department of Pharmaceutical Medicine, School of Pharmaceutical Education and Research, JamiaHamdard, New Delhi-110062, India.
Curr Drug Targets. 2021;22(6):685-720. doi: 10.2174/1389450121999201209201004.
Alzheimer's disease is a common and most chronic neurological disorder (NDs) associated with cognitive dysfunction. Pathologically, Alzheimer's disease (AD) is characterized by the presence of β-amyloid (Aβ) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, however, persistence oxidative-nitrative stress, endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory cytokines, pro-apoptotic proteins along with altered neurotransmitters level are common etiological attributes in its pathogenesis. Rivastigmine, memantine, galantamine, and donepezil are FDA approved drugs for symptomatic management of AD, whereas tacrine has been withdrawn because of hepatotoxic profile. These approved drugs only exert symptomatic relief and exhibit poor patient compliance. In the current scenario, the number of published evidence shows the neuroprotective potential of naturally occurring bioactive molecules via their antioxidant, anti-inflammatory, antiapoptotic and neurotransmitter modulatory properties. Despite their potent therapeutic implications, concerns have arisen in context to their efficacy and probable clinical outcome. Thus, to overcome these glitches, many heterocyclic and cyclic hydrocarbon compounds inspired by natural sources have been synthesized and showed improved therapeutic activity. Computational studies (molecular docking) have been used to predict the binding affinity of these natural bioactive as well as synthetic compounds derived from natural sources for the acetylcholine esterase, α/β secretase Nuclear Factor kappa- light-chain-enhancer of activated B cells (NF-kB), Nuclear factor erythroid 2-related factor 2(Nrf2) and other neurological targets. Thus, in this review, we have discussed the molecular etiology of AD, focused on the pharmacotherapeutics of natural products, chemical and pharmacological aspects and multi-targeted designed ligands (MTDLs) of synthetic and semisynthetic molecules derived from the natural sources along with some important on-going clinical trials.
阿尔茨海默病是一种常见的、最常见的慢性神经障碍（NDs），与认知功能障碍有关。从病理学上讲，阿尔茨海默病（AD）的特征是存在β-淀粉样蛋白（Aβ）斑块、过度磷酸化的 tau 蛋白和神经原纤维缠结，然而，持续的氧化-硝化应激、内质网应激、线粒体功能障碍、炎性细胞因子、促凋亡蛋白以及改变的神经递质水平是其发病机制中的常见病因属性。利伐斯的明、美金刚、加兰他敏和多奈哌齐是美国食品和药物管理局批准的用于 AD 症状管理的药物，而他克林因肝毒性而被撤回。这些批准的药物仅能缓解症状，且患者依从性较差。在当前情况下，大量已发表的证据表明，天然存在的生物活性分子通过其抗氧化、抗炎、抗凋亡和神经递质调节特性具有神经保护潜力。尽管它们具有潜在的治疗意义，但人们对它们的疗效和可能的临床结果表示担忧。因此，为了克服这些障碍，许多受天然来源启发的杂环和环状碳氢化合物已被合成，并显示出改善的治疗活性。计算研究（分子对接）已被用于预测这些天然生物活性物质以及源自天然来源的合成化合物对乙酰胆碱酯酶、α/β 分泌酶核因子 kappa-轻链增强子的结合亲和力激活 B 细胞（NF-kB）、核因子红细胞 2 相关因子 2（Nrf2）和其他神经靶点。因此，在这篇综述中，我们讨论了 AD 的分子病因，重点介绍了天然产物的药物治疗学、化学和药理学方面以及源自天然来源的合成和半合成分子的多靶点设计配体（MTDLs），以及一些正在进行的重要临床试验。
