title: In vitro and in vivo antiviral activity of 2'-fluorinated arabinosides of 5-(2-haloalkyl)uracil.
abstract: 5-(2-Fluoroethyl)-2'-deoxyuridine (FEDU), its 2'-fluoroarabinofuranosyl analog (FEFAU) and the 2'-fluoroarabinofuranosyl analog (CEFAU) of the potent anti-herpesvirus compound 5-(2-chloroethyl)-2'-deoxyuridine (CEDU) were evaluated for activity against herpes simplex virus type 1 (HSV-1) and HSV-2 in vitro and in vivo. FEDU, FEFAU and CEFAU proved to be potent and selective anti-herpesvirus agents in vitro. Their potency is evident from their low minimum inhibitory concentrations for HSV-1 and HSV-2, and their selectivity is attested by the marginal inhibition of cell proliferation at relatively high concentrations, and by the high concentrations at which DNA-, RNA- or protein synthesis in normal uninfected host cells is inhibited. Their activity spectrum is broader than that of CEDU: in addition to being highly effective against HSV-1 replication, these derivatives, in particular FEFAU, inhibit HSV-2 replication at concentrations comparable to acyclovir (ACV). In the systemic and cutaneous HSV-1 infection models in mice, FEDU, FEFAU and CEFAU were markedly less potent than CEDU in suppressing the development of lesions and in reducing the mortality rate. In HSV-2 infections in mice and in guinea pigs FEDU, FEFAU and CEFAU were virtually ineffective. CEDU, however, exerted a protective effect in these animal models, albeit at relatively high concentrations.
authors.affiliation: Sandoz Forschungsinstitut, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Rosenwirth
authors.forename: W
authors.initials: W
authors.lastname: Streicher
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: E
authors.initials: E
authors.lastname: Wanek
authors.forename: W
authors.initials: W
authors.lastname: Schwarz
authors.forename: H
authors.initials: H
authors.lastname: Griengl
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D004279:DNA, Viral / Q000096:biosynthesis; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005467:Floxuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D006561:Herpes Simplex / Q000188:drug therapy*; D051379:Mice; D008812:Mice, Hairless; D012367:RNA, Viral / Q000096:biosynthesis; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D012367:RNA, Viral; D005467:Floxuridine; C053111:5-(2-fluoroethyl)-2'-deoxyuridine; C053247:5-(2-fluoroethyl)-2'-fluoroarabinofuranosyluracil; D001086:Arabinofuranosyluracil; C047370:5-(2-chloroethyl)-2'-deoxyuridine; C053246:5-(2-chloroethyl)-2'-fluoroarabinofuranosyluracil; D003857:Deoxyuridine; D000212:Acyclovir