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

A series of 2-aryl-9-methyl-β-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 μM. Thirteen compounds B showed the excellent activity with IC(50) values of 0.11–0.76 μM and high selectivity toward AChE relative to butyrylcholinesterase (BChE), superior to galantamine (IC(50) = 0.79 μM), 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 π-π or cation-π action between the carboline ring and the phenyl rings of the residues, and the β-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-β-carboliniums emerged as novel and promising tool compounds for the development of new AChE inhibitor agents.