Abstract
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 IC50 values of 0.11–0.76 μM and high selectivity toward AChE relative to butyrylcholinesterase (BChE), superior to galantamine (IC50 = 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.
Highlights
As the most common form of adult onset dementia, Alzheimer’s disease (AD) is an age-related irreversible neurodegenerative disorder characterized by a progressive memory loss, a decline in language skills and other cognitive impairments[1]
There are four FDA-approved AChE inhibitor-type drugs for treatment of cognitive dysfunction and memory loss associated with mild-to-moderate AD21
The results suggest that β-carboline is a promising molecular framework for development of new anti-AChE agents
Summary
As the most common form of adult onset dementia, Alzheimer’s disease (AD) is an age-related irreversible neurodegenerative disorder characterized by a progressive memory loss, a decline in language skills and other cognitive impairments[1]. The results above showed that both the compounds B and A had the higher selectivity for AChE than BuChE.
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