Synthesis and antiviral activity of novel acyclic nucleoside analogues of 5-(1-azido-2-haloethyl)uracils.
We present the discovery of a novel category of 5-substituted acyclic pyrimidine nucleosides as potent antiviral agents. A series of 1-[(2-hydroxyethoxy)methyl] (5-7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] (8-10), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl] (11-13) derivatives of 5-(1-azido-2-haloethyl)uracil were synthesized and evaluated for their biological activity in cell culture. 1-[4-Hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azido-2-chloroethyl)uracil (12) was the most effective antiviral agent in the in vitro assays against DHBV (EC(50) = 0.31-1.55 microM) and HCMV (EC(50) = 3.1 microM). None of the compounds investigated showed any detectable toxicity to several stationary and proliferating host cells.
Kumar
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Department of Medical Microbiology and Immunology, Faculty of Medicine, University of Alberta, Edmonton T6G 2H7, Canada. rakesh.kumar@ualberta.ca
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Nath
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Saffran
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Tyrrell
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D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral; D004247:DNA / Q000096:biosynthesis; D004372:Ducks; D006515:Hepatitis B virus / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication
C440620:1-(4-hydroxy-3-(hydroxymethyl)-1-butyl)-5-(1-azido-2-chloroethyl)uracil; D000998:Antiviral Agents; D001386:Azides; D011741:Pyrimidine Nucleosides; D014498:Uracil; D004247:DNA