Chemoenzymatic Synthesis and Antiherpes Activity of 5-Substituted 4,6-Difluorobenzimidazoles Ribo- and 2 `-Deoxyribonucleosides / Kharitonova Maria I.,Fateev Ilja V.,Kayushin Alexei L.,Konstantinova Irina D.,Kotovskaya Svetlana K.,Andronova Valeria L.,Galegov Georgii A.,Charushin Valery N.,Miroshnikov Anatoly I. // SYNTHESIS-STUTTGART. - 2016. - V. 48, l. 3. - P. 394-406.

ISSN/EISSN:

0039-7881 / 1437-210X

Type:

Article

Abstract:

A series of 5,6-disubstituted benzimidazole nucleosides, obtained earlier, did not show any significant antiviral activity at relatively low cytotoxicity in vitro. In the course of our research we have succeeded in introducing an additional fluorine atom into the benzimidazole ring system. A new series of 4,6-difluorobenzimidazoles, bearing various groups (fluoro-, methoxy-, ethoxy-, morpholino-, and pyrrolidino-) in the 5-position of the benzene ring, have been synthesized. All these compounds proved to be substrates for recombinant E. coli purine nucleoside phosphorylase (PNP) in the transglycosylation reaction. Effective methods for the synthesis of ribo-and 2'-deoxyribonucleosides with high yields (60-90\%) have been described, and the formation of regioisomeric N3-nucleosides of benzimidazoles have been detected. The biological activity of the nucleosides obtained against herpes simplex virus type 1 (HSV-1) has been elucidated. All compounds show a low cytotoxicity in the cell culture Vero E6. 4,5,6-Trifluoro-1-(beta-D-ribofuranosyl)benzimidazole and 5-methoxy-4,6-difluoro-1-(beta-D-2'-deoxyribofuranosyl) benzimidazole proved to inhibit completely the progression of the virus cytopathic effect (CPE) at a multiplicity of infection (MOI) of 0.01 PFU/cell.

Author keywords:

drug discovery; herpes simplex virus; fluorine; nucleosides PURINE NUCLEOSIDE PHOSPHORYLASE; HUMAN CYTOMEGALOVIRUS; ANTIVIRAL ACTIVITY; MARIBAVIR; DERIVATIVES; BIOTECHNOLOGY; RECIPIENTS; EFFICACY; AGENTS; DRUGS

DOI:

10.1055/s-0035-1560911

Web of Science ID:

ISI:000369753300014

Соавторы в МНС:

Другие поля

Поле	Значение
Month	FEB
Publisher	GEORG THIEME VERLAG KG
Address	RUDIGERSTR 14, D-70469 STUTTGART, GERMANY
Language	English
EISSN	1437-210X
Keywords-Plus	PURINE NUCLEOSIDE PHOSPHORYLASE; HUMAN CYTOMEGALOVIRUS; ANTIVIRAL ACTIVITY; MARIBAVIR; DERIVATIVES; BIOTECHNOLOGY; RECIPIENTS; EFFICACY; AGENTS; DRUGS
Research-Areas	Chemistry
Web-of-Science-Categories	Chemistry, Organic
Author-Email	kharitonova-mari@rambler.ru
ResearcherID-Numbers	Miroshnikov, Anatoly/G-5017-2017 Kharitonova, Maria/L-1594-2017
Funding-Acknowledgement	Ministry of Industry and Trade of the Russian Federation (Minpromtorg of Russia) {[}11411.1003702.13.050]; Ministry of Education of the Russian Federation {[}2458]
Funding-Text	The authors are thankful to the Ministry of Industry and Trade of the Russian Federation (Minpromtorg of Russia) (State Contract No. 11411.1003702.13.050) and the Ministry of Education of the Russian Federation (Project No. 2458) for the financial support of this work. We are indebted to Dr. Tamara A. Balashova (Institute of Bioorganic Chemistry, Moscow) for assistance in the analysis of NMR spectra of new nucleosides. Dr. Roman S. Esipov for recombinant nucleoside phosphorylases for experiments.
Number-of-Cited-References	37
Usage-Count-Last-180-days	2
Usage-Count-Since-2013	5
Journal-ISO	Synthesis
Doc-Delivery-Number	DD2LG