Synthesis and antiviral activity of acyclovir-5′-(phenyl methoxy alaninyl) phosphate as a possible membrane-soluble nucleotide prodrug

We describe a synthesis of acyclovir-5′-(phenyl methoxy alaninyl) phosphate (2) from acyclovir (1). This compound was designed to act as a lipophilic, membrane-soluble prodrug of the free nucleotide. However, the biological activities of this derivative against a range of viruses indicated poor intracellular phosphate delivery, in marked contrast to the earlier successful delivery of several dideoxy anti-HIV nucleotides. Figure 1. Reagents and conditions: (i) Me2NCH(OMe)2/DMF; (ii) (PhO)(L-MeOC(O)CHMeNH)P(O)Cl, NMI/THF; (iii) Δ/nPrOH.