ABSTRACT
A series of ribo- and deoxyribonucleosides bearing 2-aminopurine as a nucleobase with 7,8-difluoro- 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (conjugated directly or through an aminohexanoyl spacer) was synthesized using an enzymatic transglycosylation reaction. Nucleosides 3-6 were resistant to deamination under action of adenosine deaminase (ADA) Escherichia coli and ADA from calf intestine. The antiviral activity of the modified nucleosides was evaluated against herpes simplex virus type 1 (HSV-1, strain L2). It has been shown that at sub-toxic concentrations, nucleoside (S)-4-[2-amino-9-(ß-D-ribofuranosyl)-purin-6-yl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine exhibit significant antiviral activity (SI > 32) on the model of HSV-1 in vitro, including an acyclovir-resistant virus strain (HSV-1, strain L2/R).
Subject(s)
Adenosine Deaminase/metabolism , Antiviral Agents/metabolism , Benzoxazines/chemistry , Purine Nucleosides/biosynthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Drug Resistance, Viral/drug effects , Escherichia coli/enzymology , Escherichia coli Proteins/metabolism , Herpesvirus 1, Human/drug effects , Humans , Purine Nucleosides/chemistry , Purine Nucleosides/pharmacology , Stereoisomerism , Vero CellsABSTRACT
Using the enzymatic transglycosylation reaction ß-d-ribo- and 2'-deoxyribofuranosides of 2-amino-5,6-difluorobenzimidazole nucleosides have been synthesized. 2-Amino-5,6-difluoro-benzimidazole riboside proved to exhibit a selective antiviral activity (selectivity index >32) against a wild strain of the herpes simplex virus type 1, as well as towards virus strains that are resistant to acyclovir, cidofovir, and foscarnet. We believe that this compound might be used for treatment of herpes infections in those cases, when acyclovir is not efficient.
Subject(s)
Antiviral Agents/chemical synthesis , Benzimidazoles/chemistry , Nucleosides/chemistry , Acyclovir/pharmacology , Antiviral Agents/pharmacology , Cidofovir , Cytosine/analogs & derivatives , Cytosine/pharmacology , Drug Resistance, Viral/drug effects , Foscarnet/pharmacology , Herpesvirus 1, Human/drug effects , Humans , Nucleosides/pharmacology , Organophosphonates/pharmacologyABSTRACT
The antiviral activity against HIV and HSV and the chemical stability of ACV phosphoramidate derivatives were studied. The phosphoramidates of ACV demonstrated moderate activity. The best compound appeared to be 9-(2-hydroxymethyl)guanine phosphoromonomorpholidate (7), which inhibited virus replication in pseudo-HIV-1 particles by 50% at 50 µM. It also inhibited replication of wild-type HSV-1 (9.7 µM) as well as an acyclovir-resistant strain (25 µM). None of the synthesised compounds showed any cytotoxicity.
