Conjugates of γ-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease.

Galina F Makhaeva,Sofya V Lushchekina,Sergey O Bachurin,Olga G Serebryakova,Natalia P Boltneva,Alexey Yu Aksinenko,Vladimir B Sokolov,Gjumrakch Aliev,George E Barreto,Ekaterina A Vikhareva,Vladimir V Grigoriev

doi:10.1038/srep13164

Abstract

Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.

Highlights

The development of novel compounds that are able to modify the pathogenesis of neurodegenerative diseases appears to be as a promising approach among different drug discovery strategies in this emerging area[1,2]
All γ -carboline-phenothiazine conjugates have been assessed as inhibitors of AChE and BChE, which are important for Alzheimer disease (AD) and/or AD-like dementia development and structurally close enzyme—CaE
Dimebon, phenothiazine and methylene blue were used as reference compounds

Summary

Introduction

The development of novel compounds that are able to modify the pathogenesis of neurodegenerative diseases appears to be as a promising approach among different drug discovery strategies in this emerging area[1,2]. It was shown that combining glutamatergic and cholinergic approaches in the symptomatic treatment of AD could be much more efficient[17] compared to the single treatment option In this regard, the design of new compounds that can interact with both of these neuromediator systems is more likely to confer better protection against neurodegeneration and compensating the deficit of cholinergic and glutamatergic functions that appeared to be key features of these diseases[19]. Significant protective effects were observed in a vitro model of ALS when both compounds are administered simultaneously[25] In this context, we previously synthesized a group of original compounds that combine γ -carboline fragment of dimebon and phenothiazine core of MB in the same structure[26,27], as a novel approach to the development of multitarget disease-modifying agents (Fig. 1). The background for selection of these biological targets were the results of the previous observations that phenothiazine derivatives including MB can effectively inhibit the enzymes of cholinesterase family[28,29,30,31] and one of the target of dimebon neuronal action is the NMDA-receptor[32]

Methods

Results

Discussion

Conclusion