Synthesis, molecular docking, and biological activity of polyfluoroalkyl dihydroazolo{[}5,1-c]{[}1,2,4]triazines as selective carboxylesterase inhibitors / Shchegol'kov Evgeny V.,Makhaeva Galina F.,Boltneva Natalia P.,Lushchekina Sofya V.,Serebryakova Olga G.,Rudakova Elena V.,Kovaleva Nadezhda V.,Burgart Yanina V.,Saloutin Victor I.,Chupakhin Oleg N.,Bachurin Sergey O.,Richardson Rudy J. // BIOORGANIC \& MEDICINAL CHEMISTRY. - 2017. - V. 25, l. 15. - P. 3997-4007.

ISSN/EISSN:

0968-0896 / 1464-3391

Type:

Article

Abstract:

To search for effective and selective inhibitors of carboxylesterase (CaE), a series of 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo{[}5,1-c]{[}1,2,4] triazines has been synthesized. Their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and CaE were investigated using the methods of enzyme kinetics and molecular docking. It was shown that the tested compounds are reversible selective CaE inhibitors of mixed type. Elongation of the polyfluoroalkyl substituent and the presence of an ester, preferably the ethoxycarbonyl group, enhance inhibitory activity toward CaE. Furthermore, the compounds with a tetrazole ring are more active against CaE than their triazole analogues. The obtained kinetic data are well explained by the results of molecular docking, according to which there is a similar orientation of triazolo-and tetrazolotriazines in the active site of CaE and the opposite one for pyrazolotriazines. In the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay, all of the studied tetrazolotriazines and some pyrazolotriazines demonstrated good antiradical activity comparable with a standard antioxidant, Trolox. The leading compounds were nonafluorobutyl substituted tetrazolo- and 7-phenylpyrazolotriazines, which possess effective and selective CaE inhibitory activity as well as additional useful radical-scavenging properties. (C) 2017 Elsevier Ltd. All rights reserved.

Author keywords:

7-Hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo{[}5,1-c]{[}1,2,4]triazines; Esterase profile; Carboxylesterase inhibitors; Molecular docking; Antioxidant activity; ABTS assay ACETYLCHOLINESTERASE INHIBITORS; ANTIMICROBIAL ACTIVITY; CATALYTIC-PROPERTIES; DERIVATIVES; MOIETY; HEPATOTOXICITY; ASSAY; BUTYRYLCHOLINESTERASE; METABOLISM; THIAZOLE

DOI:

10.1016/j.bmc.2017.05.045

Web of Science ID:

ISI:000406022200010

Соавторы в МНС:

Другие поля

Поле	Значение
Month	AUG 1
Publisher	PERGAMON-ELSEVIER SCIENCE LTD
Address	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
Language	English
EISSN	1464-3391
Keywords-Plus	ACETYLCHOLINESTERASE INHIBITORS; ANTIMICROBIAL ACTIVITY; CATALYTIC-PROPERTIES; DERIVATIVES; MOIETY; HEPATOTOXICITY; ASSAY; BUTYRYLCHOLINESTERASE; METABOLISM; THIAZOLE
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 Shchegol'kov, Evgenii/H-6790-2015 Burgart, Yanina/T-8025-2017 Makhaeva, Galina/A-9412-2014
ORCID-Numbers	Lushchekina, Sofya/0000-0002-6922-020X Shchegol'kov, Evgenii/0000-0001-6611-2855 Burgart, Yanina/0000-0001-6061-2410
Funding-Acknowledgement	Russian Foundation for Basic Research, program ``Medicinal Chemistry{''} of the Russian Academy of Sciences {[}16-03-00417]
Funding-Text	This work was partly supported by grant No 16-03-00417 of the Russian Foundation for Basic Research, program ``Medicinal Chemistry{''} of the Russian Academy of Sciences. We thank the Lomonosov Supercomputer center68 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	67
Usage-Count-Last-180-days	9
Usage-Count-Since-2013	9
Journal-ISO	Bioorg. Med. Chem.
Doc-Delivery-Number	FB3DG