5-Alkynyl Pyrimidine Nucleosides as Potent Selective Inhibitors of Varicella-Zoster Virus

A series of 5-alkynyl substituted 2′-deoxyuridine and β-D-arabinofuranosyluracil nucleosides were synthesized and evaluated for in vitro activity against varicella-zoster virus (VZV). Three promising analogues, 1-(β-D-arabinofuranosyl)-5-ethynyluracil (EYaraU), 2′-deoxy-5-prop-1-ynyluridine (PYdU) and 1-(β-D-arabinof uranosyl)-5-prop-1-ynyluracil (PYaraU) had potent activity against eight strains of VZV with IC50 values averaging 1 μM. This activity was selective for VZV as the compounds were significantly less active against herpes simplex viruses (HSV) and human cytomegalovirus (HCMV) in contrast to 2′-deoxy-5-ethynyluridine (EYdU) which is highly active against all three viruses. The ability of these compounds to inhibit the growth of Vera or MRC-5 cells was over 2 orders of magnitude less than their antiviral activity (CC50 in Vero cells 350 μM for EYaraU and >500 μM for PYdU and PYaraU and >500 μM for all 3 compounds in MRC-5 cells). Direct comparative studies showed these compounds to be more potent and more selective than acyclovir (ACV).