In vitro Anti-Herpesvirus Activities of 5-Substituted 2′-Deoxy-2′-Methylidene Pyrimidine Nucleosides

New pyrimidine deoxyribonucleoside analogues, 2′-deoxy-2′-methylideneuridine (DMDU), 2′-deoxy-2′-methylidenecytidine (DMDC), and their 5-substituted derivatives were tested for the anti-herpesvirus activities and anti-proliferative activity. E-5-(2-Bromovinyl)uracil derivative (BV-DMDU) and its cytosine congener were synthesized from 1-β-D-arabinofuranosyl- E-5-(2-bromovinyl)uracil (BV-araU). 5-Bromo, 5-iodo, 5-methyl, and 5-ethyl derivatives of DMDU and BV-DMDU showed activities against herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV). The corresponding DMDC derivatives had no or only weak antiviral activity. Among the 2′-deoxy-2′-methylidene pyrimidine nucleosides, BV-DMDU showed the most potent and selective anti-VZV activity. BV-DMDU was more potent than acyclovir, but less active than BV-araU. BV-DMDU was inactive against human diploid and tumour cells. DMDC and F-DMDC (5-fluoro derivative) were potent inhibitors of HSV-1, herpes simplex virus type 2, VZV, and human cytomegalovirus (HCMV) and also had significant anti-proliferative activity. Their potency against HCMV was better than that of ganciclovir and araC. Some DMDU derivatives also showed anti-HCMV activity, but they had anti-proliferative activity. The anti-HCMV activity of these DMDC and DMDU compounds was generally more potent than those against HSV-1 and VZV thereof, suggesting the participation of cellular kinase in their antiviral action.