Synthesis 2017; 49(05): 1043-1052
DOI: 10.1055/s-0036-1588625
paper
© Georg Thieme Verlag Stuttgart · New York

Chemoenzymatic Synthesis of Modified 2′-Deoxy-2′-fluoro-β-d-arabinofuranosyl Benzimidazoles and Evaluation of Their Activity Against Herpes Simplex Virus Type 1

Maria I. Kharitonova*
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
,
Konstantin V. Аntonov
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
,
Ilya V. Fateev
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
,
Мaria Ya. Berzina
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
,
Alexei L. Kaushin
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
,
Alexander S. Paramonov
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
,
Svetlana K. Kotovskaya
b   Postovsky Institute of Organic Synthesis, The Ural Branch of the Russian Academy of Sciences, S. Kovalevskaya/Academicheskaya St. 22/20, 620041, Ekaterinburg, Russian Federation
c   Ural Federal University named after the first President of Russia B. N. Yeltsin, Mira St. 19, 620002, Ekaterinburg, Russian Federation
,
Valeria L. Аndronova
d   D. I. Ivanovsky Institute of Virology (N. F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Healthcare of the Russian Federation), Gamaleya St. 18, 123098, Moscow, Russian Federation   Email: kharitonova-mari@rambler.ru
,
Irina D. Konstantinova
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
,
Georgiy A. Galegov
d   D. I. Ivanovsky Institute of Virology (N. F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Healthcare of the Russian Federation), Gamaleya St. 18, 123098, Moscow, Russian Federation   Email: kharitonova-mari@rambler.ru
,
Valery N. Charushin
b   Postovsky Institute of Organic Synthesis, The Ural Branch of the Russian Academy of Sciences, S. Kovalevskaya/Academicheskaya St. 22/20, 620041, Ekaterinburg, Russian Federation
c   Ural Federal University named after the first President of Russia B. N. Yeltsin, Mira St. 19, 620002, Ekaterinburg, Russian Federation
,
Anatoly I. Miroshnikov
a   Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow B-437, Russian Federation
› Author Affiliations
Further Information

Publication History

Received: 11 July 2016

Accepted after revision: 22 September 2016

Publication Date:
19 October 2016 (online)


Abstract

1-(2′-Deoxy-2′-fluoro-β-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-β-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-β-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-(β-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. сoli, was investigated. 1-(β-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.

Supporting Information

 
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