Elkotamy Mahmoud S, Elgohary Mohamed K, Alkabbani Mahmoud Abdelrahman, Hefina Mohamed M, Tawfik Haytham O, Fares Mohamed, Eldehna Wagdy M, Abdel-Aziz Hatem A
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo, 11829, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo, 11829, Egypt.
Eur J Med Chem. 2025 Feb 5;283:117158. doi: 10.1016/j.ejmech.2024.117158. Epub 2024 Dec 10.
As a complicated neurodegenerative disorder with several clinical hallmarks, Alzheimer's disease (AD) requires multi-target treatment medicines to address multiple elements of disease progression. In this study, we reported two novel series of compounds: benzofuran-based donepezil analogs (9a-i) and their pyrazole-based counterparts (11a-i) as potential dual inhibitors of AChE and BuChE with additional antioxidant properties, aiming to address multiple pathological aspects of AD simultaneously. The design strategy employed bioisosteric replacement, substituting donepezil's indanone motif with a benzofuran ring in series (9a-i) to maintain crucial hydrogen bonding interactions with the Phe295 residue in the enzyme's active site. Subsequently, the benzofuran ring underwent cleavage, yielding pyrazole-tethered hydroxyphenyl derivatives (11a-i). The biological evaluation revealed that benzofuran-based derivative 9g exhibited exceptional efficacy against both AChE and BuChE, with IC values of 0.39 and 0.51 μg/ml, respectively, although it lacked antioxidant activity. Compound 11f demonstrated dual inhibition of AChE (IC = 1.24 μg/ml) and BuChE (IC = 1.85 μg/ml) while also displaying strong DPPH free radical scavenging activity (IC = 3.15 μg/ml). In vivo toxicity studies on compound 11f revealed a favorable safety profile, with no signs of toxicity or adverse events in acute oral toxicity tests in male Wistar rats. Chronic administration of 11f resulted in negligible differences in blood profiles, hepatic enzymes, urea, creatinine, and albumin levels compared to the control group. Histopathological examination of hepatic and kidney tissues from treated rats showed normal histology without damage. In silico molecular docking analysis was performed to rationalize the design approaches and support the experimental findings. This study provides valuable insights into the development of multi-target compounds for potential Alzheimer's disease treatment.
作为一种具有多种临床特征的复杂神经退行性疾病，阿尔茨海默病（AD）需要多靶点治疗药物来应对疾病进展的多个环节。在本研究中，我们报告了两个新的化合物系列：基于苯并呋喃的多奈哌齐类似物（9a-i）及其基于吡唑的类似物（11a-i），它们是乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的潜在双重抑制剂，并具有额外的抗氧化特性，旨在同时应对AD的多个病理方面。设计策略采用生物电子等排体替换，在系列（9a-i）中用苯并呋喃环取代多奈哌齐的茚满酮基序，以维持与酶活性位点中Phe295残基的关键氢键相互作用。随后，苯并呋喃环发生裂解，产生吡唑连接的羟基苯基衍生物（11a-i）。生物学评价显示，基于苯并呋喃的衍生物9g对AChE和BuChE均表现出优异的疗效，IC值分别为0.39和0.51μg/ml，尽管它缺乏抗氧化活性。化合物11f表现出对AChE（IC = 1.24μg/ml）和BuChE（IC = 1.85μg/ml）的双重抑制作用，同时还表现出较强的二苯基苦味酰基自由基清除活性（IC = 3.15μg/ml）。对化合物11f的体内毒性研究显示出良好 的安全性，在雄性Wistar大鼠的急性口服毒性试验中没有毒性或不良事件的迹象。与对照组相比，长期给予11f导致血液指标、肝酶、尿素、肌酐和白蛋白水平的差异可忽略不计。对治疗大鼠的肝和肾组织进行组织病理学检查显示组织学正常，无损伤。进行了计算机辅助分子对接分析，以合理化设计方法并支持实验结果。本研究为开发用于潜在阿尔茨海默病治疗的多靶点化合物提供了有价值的见解。
