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

  • ACS Med Chem Lett. 2018 Mar 16;9(4):381-385. doi: 10.1021/acsmedchemlett.8b00079.
Min Luo  1 ,  Elisabetta Groaz  1 ,  Steven De Jonghe  2 ,  Robert Snoeck  2 ,  Graciela Andrei  2 ,  Piet Herdewijn  1
Affiliations
  • 1. Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
  • 2. Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49 bus 1043, 3000 Leuven, Belgium.
PMID: 29670705 DOI: 10.1021/acsmedchemlett.8b00079
Abstract

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.