Synthesis and antiviral activities of methylenecyclopropane analogs with 6-alkoxy and 6-alkylthio substitutions that exhibit broad-spectrum antiviral activity against human herpesviruses

Mark N. Prichard, John D. Williams, Gloria Komazin-Meredith, Atiyya R. Khan, Nathan B. Price, Geraldine M. Jefferson, Emma A. Harden, Caroll B. Hartline, Norton P. Peet, Terry L. Bowlin

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 varicellazoster 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.

Original languageEnglish (US)
Pages (from-to)3518-3527
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume57
Issue number8
DOIs
StatePublished - Aug 1 2013

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Herpesviridae
Human Activities
Antiviral Agents
Cytomegalovirus
Human Herpesvirus 6
Human Herpesvirus 8
Human Herpesvirus 2
Thymidine Kinase
Human Herpesvirus 1
Sulfides
Virus Diseases
Human Herpesvirus 4
Nucleosides
Hepatitis B virus
Ether
Phosphotransferases
methylenecyclopropane
alkoxyl radical
HIV
Viruses

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Prichard, Mark N. ; Williams, John D. ; Komazin-Meredith, Gloria ; Khan, Atiyya R. ; Price, Nathan B. ; Jefferson, Geraldine M. ; Harden, Emma A. ; Hartline, Caroll B. ; Peet, Norton P. ; Bowlin, Terry L. / Synthesis and antiviral activities of methylenecyclopropane analogs with 6-alkoxy and 6-alkylthio substitutions that exhibit broad-spectrum antiviral activity against human herpesviruses. In: Antimicrobial agents and chemotherapy. 2013 ; Vol. 57, No. 8. pp. 3518-3527.
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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 varicellazoster 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.",
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Synthesis and antiviral activities of methylenecyclopropane analogs with 6-alkoxy and 6-alkylthio substitutions that exhibit broad-spectrum antiviral activity against human herpesviruses. / Prichard, Mark N.; Williams, John D.; Komazin-Meredith, Gloria; Khan, Atiyya R.; Price, Nathan B.; Jefferson, Geraldine M.; Harden, Emma A.; Hartline, Caroll B.; Peet, Norton P.; Bowlin, Terry L.

In: Antimicrobial agents and chemotherapy, Vol. 57, No. 8, 01.08.2013, p. 3518-3527.

Research output: Contribution to journalArticle

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AU - Prichard, Mark N.

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AB - 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 varicellazoster 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.

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