Department of Pharmacy, School of Health Sciences, Frederick University, 1036 Nicosia, Cyprus.
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Molecules. 2022 Oct 17;27(20):6984. doi: 10.3390/molecules27206984.
Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by memory loss and cognitive impairment. Its pathology has not been fully clarified and therefore highly effective treatments have not been obtained yet. Almost all the current treatment options aim to alleviate only the symptoms and not to eliminate the disease itself. Acetylcholinesterase inhibitors are the main therapeutic agents against AD, whereas oxidative stress and inflammation have been found to be of great significance for the development and progression of neurodegeneration. In this work, ethyl nipecotate (ethyl-piperidine-3-carboxylate), a heterocyclic carboxylic acid derivative, which acts as a GABA reuptake inhibitor and has been used in research for diseases involving GABAergic neurotransmission dysfunction, was amidated with various carboxylic acids bearing antioxidant and/or anti-inflammatory properties (e.g., ferulic acid, sinapic acid, butylated hydroxycinnamic acid). Most of our compounds have significant antioxidant potency as lipid peroxidation inhibitors (IC as low as 20 μΜ), as oxidative protein glycation inhibitors (inhibition up to 57%), and act as DPPH reducing agents. Moreover, our compounds are moderate LOX inhibitors (up to 33% at 100 μΜ) and could reduce rat paw edema induced by carrageenan by up to 61%. Finally, some of them possessed inhibitory activity against acetylcholinesterase (IC as low as to 47 μΜ). Our results indicate that our compounds could have the potentiality for further optimization as multi-targeting agents directed against AD.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征是记忆力减退和认知障碍。其病理尚未完全阐明，因此尚未获得非常有效的治疗方法。目前几乎所有的治疗选择都旨在缓解症状，而不是消除疾病本身。乙酰胆碱酯酶抑制剂是治疗 AD 的主要治疗药物，而氧化应激和炎症已被发现对神经退行性变的发展和进展具有重要意义。在这项工作中，乙基烟酸盐（乙基-哌啶-3-羧酸酯），一种杂环羧酸衍生物，作为 GABA 再摄取抑制剂，已用于研究涉及 GABA 能神经传递功能障碍的疾病，与具有抗氧化和/或抗炎特性的各种羧酸（如阿魏酸、芥子酸、丁基羟基肉桂酸）酰胺化。我们的大多数化合物具有显著的抗氧化能力，作为脂质过氧化抑制剂（IC 低至 20 μΜ），作为氧化蛋白糖基化抑制剂（抑制高达 57%），并作为 DPPH 还原剂。此外，我们的化合物是中等 LOX 抑制剂（在 100 μΜ 时高达 33%），可将角叉菜胶诱导的大鼠足肿胀减少多达 61%。最后，其中一些对乙酰胆碱酯酶具有抑制活性（IC 低至 47 μΜ）。我们的结果表明，我们的化合物有可能作为针对 AD 的多靶点药物进一步优化。
