Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities

• Published in: Bioorganic & medicinal chemistry 2016-02, Vol.24 (4), p.672-680
• Main Authors: Luo, Wen, Chen, Ying, Wang, Ting, Hong, Chen, Chang, Li-Ping, Chang, Cong-Cong, Yang, Ya-Cheng, Xie, Song-Qiang, Wang, Chao-Jie
• Format: Article
• Language: English
• Subjects: Animals; Anti-Alzheimer agent; Butyrylcholinesterase - metabolism; Catalytic Domain - drug effects; Cell Survival; Cholinesterase; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterases - metabolism; Cytotoxicity; Dose-Response Relationship, Drug; Drug Design; Enzyme Activation - drug effects; Flavonoid derivatives; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; Hep G2 Cells; Humans; Models, Molecular; Molecular modeling; Molecular Structure; PC12 Cells; Rats; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.12.031

Eighteen 7-aminoalkyl-substituted flavonoid derivatives were synthesized and evaluated as potential cholinesterase inhibitors, these compounds (5a–5r) exhibited better inhibitory activity than our previously reported compounds. They showed a mixed-type inhibition for AChE and did not affect PC12 and HepG2 cell viability at the concentration of 10μM. [Display omitted] A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a–5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64μM for AChE and 0.42μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a–5r) did not affect PC12 and HepG2 cell viability at the concentration of 10μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer’s disease.