Chemoenzymatic Synthesis of Modified 2 `-Deoxy-2 `-fluoro-beta-D-arabinofuranosyl Benzimidazoles and Evaluation of Their Activity Against Herpes Simplex Virus Type 1 / Kharitonova Maria I.,Antonov Konstantin V.,Fateev Ilya V.,Berzina Maria Ya.,Kaushin Alexei L.,Paramonov Alexander S.,Kotovskaya Svetlana K.,Andronova Valeria L.,Konstantinova Irina D.,Galegov Georgiy A.,Charushin Valery N.,Miroshnikov Anatoly I. // SYNTHESIS-STUTTGART. - 2017. - V. 49, l. 5. - P. 1043-1052.

ISSN/EISSN:

0039-7881 / 1437-210X

Type:

Article

Abstract:

1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)benzimidazoles containing 4,6-difluoro-, 4,5,6-trifluoro-, 5-fluoro-6-methoxy-, and 5-methoxy-4,6-difluorobenzimidazole fragments were synthesized by using purine nucleoside phosphorylase-catalyzed chemoenzymatic approach. As expected, enzymatic synthesis of nucleosides proceeds in lower yields of target compounds in comparison with the synthesis of ribo-and 2'-deoxyribobenzimidazoles (40-55\% vs 60-90\%). The compounds obtained were tested against the herpes simplex virus type 1, by using the Vero E6 cells. 5-Methoxy-4,6-difluoro-1-beta-D-(2'-deoxy-2'-fluoroarabinofuranosyl) benzimidazole did not show any antiviral activity, when used in nontoxic concentration. All other nucleosides proved to exhibit a selective antiherpes activity. In contrast, it was shown that benzimidazole-beta-D-arabinofuranosides of both di-and trisubstituted derivatives, having substituents in positions 4-6 of the benzene ring, as well as unsubstituted compounds, cannot be synthesized by enzymatic transglycosylation. 1-(beta-D-Arabinofuranosyl) benzimidazole was obtained through glycosylation of N-trimethylsilylbenzimidazole with 1-chloro-2,3,5-O-methoxymethyl-D-arabinose. The behavior of this compound, as inhibitor of purine nucleoside phosphorylase (PNP) E..oli, was investigated. 1-(beta-D-Arabinofuranosyl) benzimidazole was found to belong to a mixed type of inhibitors of PNP. This fact explains why all attempts to perform enzymatic arabinosylation of 4,6-di-, 5,6-di-, and 4,5,6-trisubstituted benzimidazoles failed.

Author keywords:

drug discovery; herpes simplex virus; fluorine; nucleosides NUCLEOSIDE PHOSPHORYLASES; ARABINONUCLEOSIDES; RIBONUCLEOSIDES; RESISTANCE

DOI:

10.1055/s-0036-1588625

Web of Science ID:

ISI:000398093000015

Соавторы в МНС:

Другие поля

Поле	Значение
Month	MAR
Publisher	GEORG THIEME VERLAG KG
Address	RUDIGERSTR 14, D-70469 STUTTGART, GERMANY
Language	English
EISSN	1437-210X
Keywords-Plus	NUCLEOSIDE PHOSPHORYLASES; ARABINONUCLEOSIDES; RIBONUCLEOSIDES; RESISTANCE
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 Education of the Russian Federation {[}2458]
Funding-Text	The authors are thankful 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 providing recombinant E. coli purine nucleoside phosphorylase samples, and the Ministry of Education of the Russian Federation (Project No. 2458) for the financial support of this work.
Number-of-Cited-References	31
Usage-Count-Last-180-days	2
Usage-Count-Since-2013	4
Journal-ISO	Synthesis
Doc-Delivery-Number	EQ5AK