ABSTRACT
Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4'-chloromethyl-2'-deoxy-2'-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4'-modified-2'-deoxy-2'-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.
Subject(s)
Antiviral Agents/chemical synthesis , Deoxycytidine/analogs & derivatives , Deoxyribonucleosides/chemical synthesis , Prodrugs/chemical synthesis , Animals , Antiviral Agents/pharmacology , Cell Line, Tumor , Chikungunya virus/drug effects , Chikungunya virus/growth & development , Cricetulus , Dengue Virus/drug effects , Dengue Virus/growth & development , Deoxycytidine/chemical synthesis , Deoxycytidine/pharmacology , Deoxyribonucleosides/pharmacology , Epithelial Cells/drug effects , Epithelial Cells/virology , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Microbial Sensitivity Tests , Primary Cell Culture , Prodrugs/pharmacology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/growth & development , T-Lymphocytes/drug effects , T-Lymphocytes/virology , Treatment Failure , Virus Replication/drug effects , West Nile virus/drug effects , West Nile virus/growth & development , Zika Virus/drug effects , Zika Virus/growth & developmentABSTRACT
The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion. Selected compounds were studied under negative-stain electron microscopy for their ability to disrupt the HBV capsid formation. Structures were modeled into a binding site recently identified in the HBV capsid protein for similar molecules to rationalize the structure-activity relationships for this family of compounds.
Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , Capsid/metabolism , Hepatitis B virus/drug effects , Virus Assembly/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Benzamides/chemical synthesis , Benzamides/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Chlorocebus aethiops , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Vero CellsABSTRACT
New modifications to the scaffold of previously reported HBV capsid assembly effectors such as BAY 41-4109, HAP-12 and GLS4 were explored. The anti-HBV activity in the HepAD38 system, and cytotoxicity profiles of each of the new compounds has been assessed. Among them, five new iodo- and bromo-heteroarylpyrimidines analogs displayed anti-HBV activity in the low micromolar range.
