title: Synthesis and antiviral activities of methylenecyclopropane analogs with 6-alkoxy and 6-alkylthio substitutions that exhibit broad-spectrum antiviral activity against human herpesviruses.
abstract: Methylenecyclopropane nucleosides have been reported to be active against many of the human herpesviruses. The most active compound of this class is cyclopropavir (CPV), which exhibits good antiviral activity against human cytomegalovirus (HCMV), Epstein-Barr virus, both variants of human herpesvirus 6, and human herpesvirus 8. CPV has two hydroxymethyl groups on the methylenecyclopropane ring, but analogs with a single hydroxymethyl group, such as the prototypical (S)-synguanol, are also active and exhibit a broader spectrum of antiviral activity that also includes hepatitis B virus and human immunodeficiency virus. Here, a large set of monohydroxymethyl compounds with ether and thioether substituents at the 6 position of the purine was synthesized and evaluated for antiviral activity against a range of human herpesviruses. Some of these analogs had a broader spectrum of antiviral activity than CPV, in that they also inhibited the replication of herpes simplex viruses 1 and 2 and varicella-zoster virus. Interestingly, the antiviral activity of these compounds appeared to be dependent on the activity of the HCMV UL97 kinase but was relatively unaffected by the absence of thymidine kinase activity in HSV. These data taken together indicate that the mechanism of action of these analogs is distinct from that of CPV. They also suggest that they might be useful as broad-spectrum antiherpesvirus agents and may be effective in the treatment of resistant virus infections.
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, USA. mprichard@peds.uab.edu
authors.forename: Mark N
authors.initials: MN
authors.lastname: Prichard
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.forename: Gloria
authors.initials: G
authors.lastname: Komazin-Meredith
authors.forename: Atiyya R
authors.initials: AR
authors.lastname: Khan
authors.forename: Nathan B
authors.initials: NB
authors.lastname: Price
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: Jefferson
authors.forename: Emma A
authors.initials: EA
authors.lastname: Harden
authors.forename: Caroll B
authors.initials: CB
authors.lastname: Hartline
authors.forename: Norton P
authors.initials: NP
authors.lastname: Peet
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology; D004279:DNA, Viral / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006564:Herpesviridae / Q000187:drug effects* / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000502:physiology; D015654:Herpesvirus 6, Human / Q000187:drug effects / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D004279:DNA, Viral; D011684:Purine Nucleosides; C508672:methylenecyclopropane; C470351:synguanol; D006147:Guanine; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase