Synthesis and evaluation of 4-hydroxyl aurone derivatives as multifunctional agents for the treatment of Alzheimer’s disease

• Published in: Bioorganic & medicinal chemistry 2016-05, Vol.24 (10), p.2342-2351
• Main Authors: Li, Yan, Qiang, Xiaoming, Luo, Li, Li, Yuxing, Xiao, Ganyuan, 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; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacokinetics; Antioxidants - pharmacology; Aurone derivatives; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - pharmacokinetics; Benzofurans - pharmacology; Blood-Brain Barrier - metabolism; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacokinetics; Chelating Agents - pharmacology; Copper - metabolism; Humans; Models, Molecular; Monoamine oxidase; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacokinetics; Monoamine Oxidase Inhibitors - pharmacology; Multifunctional agents; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - metabolism; Protein Aggregates - drug effects; Swine; β-Amyloid aggregation
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.04.012

[Display omitted] A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu2+-induced Aβ1–42 aggregation with 99.2% and 84.0% at 25μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC50 values of 0.271μM and 0.393μM, respectively. However the 6-methoxyl aurones 15a–c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood–brain barrier (BBB) permeabilities in vitro.