Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety

A series of 5-substituted uracil nucleoside derivatives with a 1(1'S,2'R)-[ 1',2'-bis(hydroxymethyl)-cycloproplyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among t he compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella tester virus (VZV) activity over acyclovir (ACV) but were l ess potent than ACV against herpes symplex virus type-1 (HSV-1). IC50 value s for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 m u g/mL for I derivatives and 3.4 mu g/mL for ACV. The most potent compound, (1'S,2'R)-5-[(E)-2-bromoethenyl]-1-[[1', (hydroxymethyl)cycloprop-1'-yl]me thyl]-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 r ats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluraci l (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BV U), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after ora l administration.