title: Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety.
abstract: A series of 5-substituted uracil nucleoside derivatives with a 1(1'S, 2'R)-[1',2'-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC(50) values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 microg/mL for I derivatives and 3.4 microg/mL for ACV. The most potent compound, (1'S,2'R)-5-[(E)-2-bromoethenyl]-1-[[1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]-2,4-(1H, 3H)-pyrimidinedione (3a), was 40-60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.
authors.affiliation: Pharmaceutical Research Laboratories, Ajinomoto Company, Inc., 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Onishi
authors.forename: C
authors.initials: C
authors.lastname: Mukai
authors.forename: R
authors.initials: R
authors.lastname: Nakagawa
authors.forename: T
authors.initials: T
authors.lastname: Sekiyama
authors.forename: M
authors.initials: M
authors.lastname: Aoki
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Nakazawa
authors.forename: N
authors.initials: N
authors.lastname: Ono
authors.forename: Y
authors.initials: Y
authors.lastname: Ohmura
authors.forename: S
authors.initials: S
authors.lastname: Iwayama
authors.forename: M
authors.initials: M
authors.lastname: Okunishi
authors.forename: T
authors.initials: T
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes / Q000737:chemistry; D018259:Herpesvirus 1, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D014498:Uracil / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D014498:Uracil