Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer’s disease

• Published in: Bioorganic & medicinal chemistry 2018-12, Vol.26 (23-24), p.6115-6127
• Main Authors: Song, Qing, Li, Yan, Cao, Zhongcheng, Liu, Hongyan, Tian, Chaoquan, Yang, Ziyi, Qiang, Xiaoming, Tan, Zhenghuai, Deng, Yong
• Format: Article
• Language: English
• Subjects: 2,5-Dihydroxyterephthalamide derivatives; Acetylcholinesterase - metabolism; Acetylcholinesterase inhibitors; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-neuroinflammatory agents; Antioxidant; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Aβ aggregation inhibitors; Butyrylcholinesterase - metabolism; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacology; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - metabolism; Phthalimides - chemical synthesis; Phthalimides - chemistry; Phthalimides - pharmacology; Protein Aggregates - drug effects; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.11.015

[Display omitted] A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC50 = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ1–42 aggregation (IC50 = 3.05 μM) and Cu2+-induced Aβ1–42 aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu2+-induced Aβ1–42 aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.