title: Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides.
abstract: A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC50 of ∼10 μM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 μM.
authors.affiliation: Institut de Chimie Organique et Analytique, UMR 7311 CNRS, Université d'Orléans, 45067 Orléans, France.
authors.forename: Manabu
authors.initials: M
authors.lastname: Hamada
authors.forename: Vincent
authors.initials: V
authors.lastname: Roy
authors.forename: Tamara R
authors.initials: TR
authors.lastname: McBrayer
authors.forename: Tony
authors.initials: T
authors.lastname: Whitaker
authors.forename: Cesar
authors.initials: C
authors.lastname: Urbina-Blanco
authors.forename: Steven P
authors.initials: SP
authors.lastname: Nolan
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Luigi A
authors.initials: LA
authors.lastname: Agrofoglio
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014780:Viruses / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D011355:Prodrugs
keywords: Antiviral properties; CC(50); DNA; EC(50); HSV; MCC; MDCK; Madin–Darby canine kidney; Modified heterocycles; Nucleosides; Olefin cross metathesis; RNA; Synthesis; VSV; VV; VZV; compound concentration affording 50% inhibition of cell growth; compound concentration affording 50% inhibition of the viral cytopathicity; deoxyribonucleic acid; herpes simplex virus; minimum cytotoxic concentration required to afford a microscopically detectable alteration of cell morphology; ribonucleic acid; vaccinia virus; varicella zoster virus; vesicular stomatitis virus
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