New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity

Abstract

New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC₅₀'s of 0.15-1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug.

Keywords: 5-Azacytosine; Acyclic nucleoside phosphonates; Antivirals; HPMP-5-azaC; Open-ring; PME-azaC; PMEO-DAPy; Phosphonate; Prodrug.

Graphical abstract

Fig. 1

Structures of “open-ring” acyclic nucleoside phosphonates.

Fig. 2

Examples of acyclic nucleoside phosphonates with 5-azacytosine base.

Scheme 1

Synthesis of various prodrug structures derived from 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (1).

Scheme 2

Synthesis of POM and POC esters derived from 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (6).

Scheme 3

Synthesis of phosphoramidate prodrugs of 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (6).

Scheme 4

Synthesis of alkoxyalkyl esters of 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (6).

Scheme 5

Synthesis of tyrosine-based prodrugs of 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (6).

Fig. 3

General numbering scheme for assignment of NMR signals.