acyclovir and phosphoramidic-acid

We report the synthesis of a series of novel 2'-deoxy-2',2'-difluoro-5-halouridines and their corresponding phosphoramidate ProTides. All compounds were evaluated for antiviral activity and for cellular toxicity. Interestingly, 2'-deoxy-2',2'-difluoro-5-iodo- and -5-bromo-uridines showed selective activity against feline herpes virus replication in cell culture due to a specific recognition (activation) by the virus-encoded thymidine kinase.

Topics: Amides; Animals; Antineoplastic Agents; Antiviral Agents; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Floxuridine; Hepacivirus; Humans; Mice; Microbial Sensitivity Tests; Molecular Conformation; Phosphoric Acids; Stereoisomerism; Structure-Activity Relationship; Virus Replication

Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated. ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types -1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.

Topics: Acyclovir; Amides; Amino Acids; Anti-HIV Agents; Benzene; Catalytic Domain; Cathepsin A; Cell Line; Enzyme Activation; Esters; HIV-1; Humans; Models, Molecular; Nerve Tissue Proteins; Phosphoric Acids; Simplexvirus

Novel phosphoramidates of acyclovir have been prepared and evaluated in vitro against acyclovir-sensitive and -resistant herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV). Unlike the parent nucleoside these novel phosphate prodrugs retain antiviral potency versus the ACV-resistant virus strain, suggesting an efficient bypass of the viral thymidine kinase.

Topics: Acyclovir; Amides; Antiviral Agents; Herpesvirus 1, Human; Herpesvirus 2, Human; Herpesvirus 3, Human; Humans; Molecular Structure; Phosphoric Acids; Prodrugs; Thymidine Kinase

We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), designed to act as membrane soluble prodrugs of the free nucleotide. The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains. The phosphoramidate derivative bearing the amino acid alpha,alpha-dimethylglycine showed poor activity in all cell lines tested. It appears that successful kinase bypass by phosphoramidates is highly dependent on the nucleoside analogue, amino acid and ester structure, as well as the cell line to which the drugs are exposed.

Topics: Acyclovir; Amides; Antiviral Agents; Bromodeoxyuridine; Cell Line; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Fibroblasts; Herpesvirus 3, Human; Humans; Lung; Molecular Structure; Phosphoric Acids; Simplexvirus; Structure-Activity Relationship; Vaccinia virus; Vesicular stomatitis Indiana virus