Mary Wilson
Well-known member
August 16 2023
https://doi.org/10.1021/acs.jmedchem.3c00545
Uma S. Singh,* Ananda K. Konreddy, Yugandhar Kothapalli, Dongmei Liu, Megan G. Lloyd,
Vidya Annavarapu, Catherine A. White, Michael. G. Bartlett, Jennifer F. Mo at, and Chung K. Chu*
ABSTRACT: 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
identi ed β-L-5-((E)-2-bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxo-
lane-4-yl))uracil (L-BHDU, 1), which had signi cant anti-VZV activity. In this
communication, we report the synthesis and evaluation of numerous L-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
ester L-BHDU prodrugs (L-phenylalanine, 16, and L-valine, 17) had a potent
antiviral activity with EC50 values of 0.028 and 0.030 μM, respectively. The
phosphate ester prodrugs POM-L-BHDU-MP and POC-L-BHDU-MP had a
signi cant anti-VZV activity with EC50 values 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.
https://doi.org/10.1021/acs.jmedchem.3c00545
Uma S. Singh,* Ananda K. Konreddy, Yugandhar Kothapalli, Dongmei Liu, Megan G. Lloyd,
Vidya Annavarapu, Catherine A. White, Michael. G. Bartlett, Jennifer F. Mo at, and Chung K. Chu*
ABSTRACT: 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
identi ed β-L-5-((E)-2-bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxo-
lane-4-yl))uracil (L-BHDU, 1), which had signi cant anti-VZV activity. In this
communication, we report the synthesis and evaluation of numerous L-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
ester L-BHDU prodrugs (L-phenylalanine, 16, and L-valine, 17) had a potent
antiviral activity with EC50 values of 0.028 and 0.030 μM, respectively. The
phosphate ester prodrugs POM-L-BHDU-MP and POC-L-BHDU-MP had a
signi cant anti-VZV activity with EC50 values 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.