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

作者：Marcela Krečmerová, Antonı́n Holý, Graciela Andreï, Karel Pomeisl, Tomáš Tichý, Petra Břehová, Milena Masojı́dková, Martin Dračínský, Radek Pohl, Geneviève Laflamme, Lieve Naesens, Hon C. Hui, Tomáš Cihlář, Johan Neyts, Erik De Clercq, Jan Balzarini, Robert Snoeck · 发表于：Journal of Medicinal Chemistry · 年份：2010 · DOI：10.1021/jm901828c · 被引用次数：32 · 研究领域：Poxvirus research and outbreaks、Herpesvirus Infections and Treatments、HIV/AIDS drug development and treatment

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.