9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment

Galina F. Makhaeva; Sofya V. Lushchekina; Natalia P. BoltnevaOlga G. SerebryakovaElena V. RudakovaAlexey A. UstyugovSergey O. BachurinAlexander V. ShchepochkinOleg N. ChupakhinValery N. CharushinRudy J. Richardson

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9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment

机译：9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment

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Graphical abstract Display Omitted Highlights ? 9-Aryl- N -methyl-9,10-dihydroacridines (9-aryl-NMDHAs) are radical scavengers. ? 9-Aryl- N -methyl-acridinium tetrafluoroborates are cholinesterase inhibitors. ? 9-Heterocyclic amino-NMDHAs are radical scavengers and cholinesterase inhibitors. Abstract We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) using the methods of enzyme kinetics and molecular docking. Antioxidant activity of the compounds was determined using the 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS + ) radical decolorization assay as their ability to scavenge free radicals. Analysis of the esterase profiles and antiradical activities of the acridine derivatives showed that 9-aryl(heteroaryl)- N -methyl-9,10-dihydroacridines have a high radical-scavenging activity but low potency as AChE and BChE inhibitors, whereas 9-aryl(heteroaryl)- N -methyl-acridinium tetrafluoroborates effectively inhibit cholinesterases but do not exhibit antiradical activity. In contrast, a group of derivatives of 9-heterocyclic amino- N -methyl-9,10-dihydroacridine has been found that combine effective inhibition of AChE and BChE with rather high radical-scavenging activity. The results of molecular docking well explain the observed features in the efficacy, selectivity, and mechanism of cholinesterase inhibition by the acridine derivatives. Thus, in a series of acridine derivatives we have found compounds possessing dual properties of effective and selective cholinesterase inhibition together with free radical scavenging, which makes promising the use of the acridine scaffold to create multifunctional drugs for the therapy of neurodegenerative diseases.

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《Bioorganic and medicinal chemistry》 |2017年第21期|5981-5994|共14页
作者
Galina F. Makhaeva; Sofya V. Lushchekina; Natalia P. BoltnevaOlga G. SerebryakovaElena V. RudakovaAlexey A. UstyugovSergey O. BachurinAlexander V. ShchepochkinOleg N. ChupakhinValery N. CharushinRudy J. Richardson;
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作者单位

Institute of Physiologically Active Compounds Russian Academy of Sciences;

Institute of Organic Synthesis of the Russian Academy of Sciences;

Department of Environmental Health Sciences, University of Michigan;

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正文语种英语
中图分类药学;
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9-Heterocyclic amino-N-methyl-9; 10-dihydroacridines; Esterase profile; Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; Molecular docking; Antioxidant activity;

9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment

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