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)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). IC50 values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 μg/mL for I derivatives and 3.4 μg/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-β-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.