Medicinal Chemistry of Phosphonate Prodrugs for Antiviral Therapy

Considerable attention has been focused on the development of phosphonate-containing drugs for application in many therapeutic areas. However phosphonate diacids are deprotonated at physiological pH and thus phosphonate-containing drugs are not ideal for oral administration, an extremely desirable requisite for the treatment of chronic diseases. To overcome this limitation several prodrug structures of biologically active phosphonate analogues have been developed. The rationale behind the design of such agents is to achieve temporary blockade of the free phosphonic functional group until their systemic absorption and delivery, allowing the release of the active drug only once at the target. In this paper, an overview of acyclic and cyclic nucleoside phosphonate prodrugs designed as antiviral agents is presented. Introduction to acyclic and cyclic nucleoside phosphonate prodrugs Nucleoside analogues are synthetic compounds that are structurally similar to natural nucleosides, the building blocks of RNA and DNA. Once inside the cell, nucleoside analogues undergo (often three sequential) phosphorylation steps by viral and cellular kinases to generate