Czarnecka Kamila, Girek Małgorzata, Maciejewska Karolina, Skibiński Robert, Jończyk Jakub, Bajda Marek, Kabziński Jacek, Sołowiej Przemysław, Majsterek Ireneusz, Szymański Paweł
a Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy , Medical University of Lodz , Lodz , Poland.
b Department of Medicinal Chemistry, Faculty of Pharmacy , Medical University of Lublin , Lublin , Poland.
J Enzyme Inhib Med Chem. 2017 Dec;33(1):158-170. doi: 10.1080/14756366.2017.1406485.
Alzheimer's disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of β-amyloid (Aβ), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC value of 0.052 µM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC values from 0.071 to 0.797 µM. Compound 3b exhibited strong Aβ aggregation inhibitory effect with 25.7% at 5 µM to 92.8% at 100 µM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment.
阿尔茨海默病（AD）是最常见的进行性脑神经元变性形式，也是痴呆最主要的病因。遗憾的是，AD的病因尚未完全明确，但不同因素与AD的发展相关，如乙酰胆碱水平低、β-淀粉样蛋白（Aβ）聚集、tau蛋白过度磷酸化、氧化应激和炎症等。该研究包括2,3-二氢-1H-环戊并[b]喹啉与5,6-二氯烟酸及合适连接体衍生物的有机合成，作为治疗AD的多功能药物。之后进行了自诱导淀粉样β蛋白聚集、乙酰胆碱酯酶和丁酰胆碱酯酶抑制研究以及分子对接研究。结果表明，3b化合物表现出最佳的乙酰胆碱酯酶抑制活性，IC值为0.052µM，与对照相比更低。此外，所有合成化合物均表现出良好的丁酰胆碱酯酶抑制活性，IC值在0.071至0.797µM之间。化合物3b在5µM时对Aβ聚集的抑制作用为25.7%，在100µM时为92.8%，同时具有良好的抗炎作用。因此，新化合物可为作为AD治疗的多靶点导向药物的进一步开发创造新的前景。
