New 2-Aryl-9-methyl-β-carbolinium salts as Potential Acetylcholinesterase Inhibitor agents: Synthesis, Bioactivity and Structure-Activity Relationship

作者：Zhou, Bohang; Zhang, Bingyu; Li, Xingqiang; Liu, Xiuxiu; Li, Hui; Li, Ding; Cui, Zhiming; Geng, Huiling^*; Zhou, Le^*

来源：Scientific Reports, 2018, 8(1): 1559.

DOI：10.1038/s41598-018-19999-3

• BETA-CARBOLINE ALKALOIDS
• ALZHEIMERS-DISEASE
• CHOLINESTERASE-INHIBITORS
• BIOLOGICAL EVALUATION
• BUTYRYLCHOLINESTERASE
• DESIGN
• DERIVATIVES
• TOXINS
• DRUGS

A series of 2-aryl-9-methyl-beta-carbolinium bromides (B) were synthesized and explored for anti-acetylcholinesterase (AChE) activities in vitro, action mechanism and structure-activity relationship. All the compounds B along with their respective 3,4-dihydro intermediates (A) presented anti-AChE activity at 10 mu M. Thirteen compounds B showed the excellent activity with IC50 values of 0.11-0.76 mu M and high selectivity toward AChE relative to butyrylcholinesterase (BChE), superior to galantamine (IC50 = 0.79 mu M), a selective AChE inhibitor drug. Kinetic analysis showed that the action mechanisms of both compounds B and A are a competitive inhibition model. Structure-activity relationship analyses showed that the C = N+ moiety is a determinant for the activity. Substituents at 6, 7 or 4' site, the indole-N-alkyl and the aromatization of the C-ring can significantly improve the activity. Molecular docking studies showed that the compounds could combine with the active site of AChE by the p-p or cation-p action between the carboline ring and the phenyl rings of the residues, and the beta-carboline moiety is embedded in a cavity surrounded by four aromatic residues of Trp86, Tyr337, Trp439 and Tyr449. The present results strongly suggest that the para-position of the D-ring should be a preferred modification site for further structural optimization design. Thus, 2-aryl-9-methyl-beta-carboliniums emerged as novel and promising tool compounds for the development of new AChE inhibitor agents.

• 出版日期2018-1-24
• 单位西北农林科技大学