title: Antiviral activity of various 1-(2'-deoxy-β-D-lyxofuranosyl), 1-(2'-fluoro-β-D-xylofuranosyl), 1-(3'-fluoro-β-D-arabinofuranosyl), and 2'-fluoro-2',3'-didehydro-2',3'-dideoxyribose pyrimidine nucleoside analogues against duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) replication.
abstract: Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2'-fluoroxylofuranosyl, 3'-fluoroarabinofuranosyl, and 2'-fluoro-2',3'-didehydro-2',3'-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d-lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2',3'-dideoxy-2',3'-didehydro-2'-fluorothymidine (48), and 2',3'-dideoxy-2',3'-didehydro-2'-fluoro-5-ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC(50) values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 μM, respectively. Compounds 23, 25, 39, 48, and 49 (EC(50) = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 μM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC(50) of 4.1 μM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 μM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.
authors.affiliation: Department of Laboratory Medicine and Pathology, 1-71 Medical Sciences Building, Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Naveen C
authors.initials: NC
authors.lastname: Srivastav
authors.forename: Neeraj
authors.initials: N
authors.lastname: Shakya
authors.forename: Michelle
authors.initials: M
authors.lastname: Mak
authors.forename: Babita
authors.initials: B
authors.lastname: Agrawal
authors.forename: D Lorne
authors.initials: DL
authors.lastname: Tyrrell
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D004372:Ducks; D015611:Hepatitis B Virus, Duck / Q000187:drug effects* / Q000502:physiology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D009154:Mutation; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D019259:Lamivudine