Synthesis of Ester Prodrugs of 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) as Anti-Poxvirus Agents

Abstract

9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis of their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, and prodrugs based on peptidomimetics. Most HPMPDAP prodrugs were synthesized in the form of monoesters as well as the corresponding cyclic phosphonate esters. The activity was evaluated not only against vaccinia virus but also against different herpes viruses. The most potent and active prodrugs against vaccinia virus were the alkoxyalkyl ester derivatives of HPMPDAP, with 50% effective concentrations 400-600-fold lower than those of the parent compound. Prodrugs based on peptidomimetics, the 2,2,2-trifluoroethyl, the POM, and the butylsalicylyl derivatives, were able to inhibit vaccinia virus replication at 50% effective concentrations that were equivalent or ∼10-fold lower than those observed for the parent compounds.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…A similar procedure was used by Krecmerova et al 46 for the synthesis of the 2,6-diaminopurine HPMPC (HPMPC-DAP) POM-monoester prodrug 84 by reaction of 83 with POM-Cl in the presence of DCMC (Scheme 24). …”

“…This strategy was also used by Krecmerova et al 46 for the synthesis of the alkoxyalkyl prodrugs of 2,6-diaminopurine HPMP analog (HPMPDAP). Pure trans- cHPMPDAP 283 was first obtained by reacting HPMPDAP with DCC and DCMC.…”

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…The acyclic nucleotide analogue based on 2,6-diaminopurine has been further modified as its POM ( 58 ) and HDP derivatives [112], suggesting that virtually any ester (vide supra) or amide (vide infra) might be employed to obtain derivatives of the cyclic esters available from nucleotide analogues such as cidofovir.…”

Nucleoside and Nucleotide Analogues for the Treatment of Herpesvirus Infections: Current Stage and New Prospects in the Field of Acyclic Nucleoside Phosphonates

“…2,6diaminopurine counterpart of HPMPA, (S)-HPMPDAP. Recently, a detailed investigation of this compound and its ester prodrugs has been performed (Krečmerová et al, 2010a). This research, originally targeted to antipoxvirus agents, also selected, among others, several candidates with excellent antiherpetic effects.…”