Discovery of 4′-OH-flurbiprofen Mannich base derivatives as potential Alzheimer’s disease treatment with multiple inhibitory activities

• Published in: Bioorganic & medicinal chemistry 2019-03, Vol.27 (6), p.991-1001
• Main Authors: Liu, Hongyan, Qiang, Xiaoming, Song, Qing, Li, Wei, He, Yuxi, Ye, Chanyuan, Tan, Zhenghuai, Deng, Yong
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Anti-neuroinflammatory agents; Antioxidant activity; Antioxidants - chemistry; Antioxidants - pharmacokinetics; Antioxidants - pharmacology; Aβ aggregation inhibitor; Blood-Brain Barrier - metabolism; Cell Line; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacokinetics; Cholinesterase Inhibitors - pharmacology; Drug Design; Drug Discovery; Electrophorus; Flurbiprofen - analogs & derivatives; Flurbiprofen - pharmacokinetics; Flurbiprofen - pharmacology; Flurbiprofen Mannich bases; Humans; Mannich Bases - chemistry; Mannich Bases - pharmacokinetics; Mannich Bases - pharmacology; Molecular Docking Simulation; Multifunctional agents; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - metabolism; Protein Aggregates - drug effects; Rats; Swine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.01.040

[Display omitted] A series of 4′-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.