Varicella zoster virus (VZV) establishes lifelong infection
after
primary disease and can reactivate. Several drugs are approved to
treat VZV diseases, but new antivirals with greater potency are needed.
Previously, we identified β-l-5-((E)-2-bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil
(l-BHDU,1), which had significant anti-VZV
activity. In this communication, we report the synthesis and evaluation
of numerousl-BHDU prodrugs: amino acid esters (14–26), phosphoramidates (33–34), long-chain lipids (ODE-l-BHDU-MP,38, and HDP-l-BHDU-MP,39), and phosphate ester
prodrugs (POM-l-BHDU-MP,41, and POC-l-BHDU-MP,47). The amino acid esterl-BHDU
prodrugs (l-phenylalanine,16, andl-valine,17) had a potent antiviral activity with EC50values of 0.028 and 0.030 μM, respectively. The phosphate
ester prodrugs POM-l-BHDU-MP and POC-l-BHDU-MP had
a significant anti-VZV activity with EC50values of 0.035
and 0.034 μM, respectively, and no cellular toxicity (CC50> 100 μM) was detected. Out of these prodrugs,
ODE-l-BHDU-MP (38) and POM-l-BHDU-MP
(41) were selected for further evaluation in future studies.