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

ABSTRACT: A series of 2-aryl-9-methyl-?-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??M. Thirteen compounds B showed the excellent activity with IC50 values of 0.11-0.76??M and high selectivity toward AChE relative to butyrylcholinesterase (BChE), superior to galantamine (IC50?=?0.79??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 ?-? or cation-? action between the carboline ring and the phenyl rings of the residues, and the ?-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-?-carboliniums emerged as novel and promising tool compounds for the development of new AChE inhibitor agents.

SUBMITTER: Zhou B 

PROVIDER: S-EPMC5784158 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature