9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment / Makhaeva Galina F.,Lushchekina Sofya V.,Boltneva Natalia P.,Serebryakova Olga G.,Rudakova Elena V.,Ustyugov Alexey A.,Bachurin Sergey O.,Shchepochkin Alexander V.,Chupakhin Oleg N.,Charushin Valery N.,Richardson Rudy J. // BIOORGANIC \& MEDICINAL CHEMISTRY. - 2017. - V. 25, l. 21. - P. 5981-5994.

ISSN/EISSN:

0968-0896 / 1464-3391

Type:

Article

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. (C) 2017 Elsevier Ltd. All rights reserved.

Author keywords:

9-Heterocyclic amino-N-methyl-9,10-dihydroacridines; Esterase profile; Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; Molecular docking; Antioxidant activity CRESYL SALIGENIN PHOSPHATE; NUCLEOPHILIC-SUBSTITUTION; POTENTIAL THERAPEUTICS; CHOLINESTERASE-INHIBITORS; HUMAN CARBOXYLESTERASES; TACRINE DERIVATIVES; COUPLING REACTIONS; ESTERASE PROFILES; DRUG-METABOLISM; PRION DISEASE

DOI:

10.1016/j.bmc.2017.09.028

Web of Science ID:

ISI:000413755600010

Соавторы в МНС:

Другие поля

Поле	Значение
Month	NOV 1
Publisher	PERGAMON-ELSEVIER SCIENCE LTD
Address	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
Language	English
EISSN	1464-3391
Keywords-Plus	CRESYL SALIGENIN PHOSPHATE; NUCLEOPHILIC-SUBSTITUTION; POTENTIAL THERAPEUTICS; CHOLINESTERASE-INHIBITORS; HUMAN CARBOXYLESTERASES; TACRINE DERIVATIVES; COUPLING REACTIONS; ESTERASE PROFILES; DRUG-METABOLISM; PRION DISEASE
Research-Areas	Biochemistry \& Molecular Biology; Pharmacology \& Pharmacy; Chemistry
Web-of-Science-Categories	Biochemistry \& Molecular Biology; Chemistry, Medicinal; Chemistry, Organic
Author-Email	rjrich@umich.edu
ResearcherID-Numbers	Lushchekina, Sofya/F-8469-2010 Makhaeva, Galina/A-9412-2014 Ustyugov, Aleksey/D-3112-2012
ORCID-Numbers	Lushchekina, Sofya/0000-0002-6922-020X Ustyugov, Aleksey/0000-0003-1977-4797
Funding-Acknowledgement	Russian Foundation for Basic Research {[}17-03-00984]; program ``Medicinal Chemistry{''} of the Russian Academy of Sciences
Funding-Text	This work was partly supported by grant No 17-03-00984 of the Russian Foundation for Basic Research and program ``Medicinal Chemistry{''} of the Russian Academy of Sciences. We thank the Lomonosov Supercomputer center83 for computational time. We are also grateful to the Center of the Collective-Access Equipment of the Institute of Physiologically Active Compounds, Russian Academy of Sciences for use of equipment (agreement no. 14.621.21.0008, ID no. RFMEFI62114X0008). The funding sources had no role in the study design; collection, analysis and interpretation of data; writing of the manuscript; or the decision to submit the article for publication.
Number-of-Cited-References	82
Usage-Count-Last-180-days	6
Usage-Count-Since-2013	6
Journal-ISO	Bioorg. Med. Chem.
Doc-Delivery-Number	FK8JY