Amidate Prodrugs of Cyclic 9‑(S)‑[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine with Potent Anti-Herpesvirus Activity

A series of amidate prodrugs of cyclic 9-[3-hydroxy-2-(phosphonomethoxy)­propyl]­adenine (cHPMPA) featuring different amino acid motifs were synthesized. All phosphonamidates derived from (S)-cHPMPA displayed a broad spectrum activity against herpesviruses with EC₅₀ values in the low nanomolar range. A phosphonobisamidate prodrug of (S)-HPMPA also exhibited a remarkably potent antiviral activity. In addition, the leucine ester prodrug of (S)-cHPMPA and phosphonobisamidate valine ester prodrug of (S)-HPMPA proved stable in human plasma. These data warrant further development of cHPMPA prodrugs, especially against human cytomegalovirus (HCMV), for which there is a high need for treatment in transplant recipients.