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

Abstract

1-(2′-Deoxy-2′-fluoro-β-<sc>d</sc>-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 <i>Vero E6</i> cells. 5-Methoxy-4,6-difluoro-1-β-<sc>d</sc>-(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-<sc>d</sc>-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-<sc>d</sc>-Arabinofuranosyl)benzimidazole was obtained through glycosylation of <i>N</i>-trimethylsilylbenzimidazole with 1-chloro-2,3,5-<i>O</i>-methoxymethyl-<sc>d</sc>-arabinose. The behavior of this compound, as inhibitor of purine nucleoside phosphorylase (PNP) <i>E. сoli</i>, was investigated<i>.</i> 1-(β-<sc>d</sc>-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.