6-azapyrimidine-2'-deoxy-4'-thionucleosides: antiviral agents against TK+ and TK- HSV and VZV strains.
The synthesis of a series of novel 1-(2-deoxy-4-thio-beta-D-erythro-pentofuranosyl)-(6-azapyrimidine) nucleosides is described. X-ray crystallographic data of the thymidine derivative allowed conformational analysis, which indicated a twist (3T2) sugar conformation. Hydrogen-bonded assemblies for the crystal structure were determined using PLATON software to allow further interpretation of the crystal packing and base interactions. The 6-azapyrimidine nucleosides described were evaluated against a range of viral strains. The thymidine analogue showed pronounced activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and vaccinia virus. This compound lost only 5- to 10-fold of its antiviral activity against thymidine kinase (TK)-deficient HSV-1 and VZV strains. These observations suggest that the compounds may not entirely depend on viral TK-catalyzed phosphorylation for antiviral activity and/or use an alternative metabolic activation pathway, and/or display a unique mechanism of antiviral action by the unmetabolized nucleoside analogue.
Maslen
Hannah L
HL
Medicinal Chemistry Division, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
Hughes
David
D
Hursthouse
Mike
M
De Clercq
Erik
E
Balzarini
Jan
J
Simons
Claire
C
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013937:Thymidine Kinase / Q000737:chemistry / Q000235:genetics*
D000998:Antiviral Agents; D011743:Pyrimidines; D013872:Thionucleosides; D013937:Thymidine Kinase