Synthesis, anti-HBV activity and renal cell toxicity evaluation of mixed phosphonate prodrugs of adefovir

A series of phosphonate ester prodrugs of adefovir incorporating l-amino (thio)acid and non-steroidal anti-inflammatory drug (NSAID) moieties were synthesized and their anti-HBV activity and renal cell toxicity were evaluated in HepG2 2.2.15 and HK-2 cells respectively. Bioactivity evaluation results revealed that this kind of adefovir prodrug have lower renal cell toxicity than adefovir dipivoxil. Compounds 8a and 8b, incorporating the NSAID ketoprofen and the l-amino acid (Val or Ile) structural fragments, exhibited more potent anti-HBV activity than adefovir dipivoxil with IC50 = 0.51 and 0.73 μM, SI = 1697.64 and 881.92 respectively. In vitro stability studies showed that the synthesized prodrugs have higher chemical and plasma stability than the positive control adefovir dipivoxil.

A series of phosphonate ester prodrugs of adefovir incorporating l-amino (thio)acid and non-steroidal anti-inflammatory drug (NSAID) moieties were synthesized, characterized and evaluated for their anti-HBV activity, renal cell toxicity and in vitro stability.Figure optionsDownload as PowerPoint slideHighlights
► A series of novel mixed phosphonate prodrugs of adefovir were prepared.
► Compounds 8a and 8b displayed more potent anti-HBV activity than adefovir dipivoxil.
► Designed compounds exhibited lower renal cell toxicity than adefovir dipivoxil.
► Designed compounds have higher stability than adefovir dipivoxil.