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

0477657 - ÚOCHB 2018 RIV GB eng J - Článek v odborném periodiku
Krečmerová, Marcela - Dračínský, Martin - Snoeck, R. - Balzarini, J. - Pomeisl, Karel - Andrei, G.
New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity.
Bioorganic & Medicinal Chemistry. Roč. 25, č. 17 (2017), s. 4637-4648. ISSN 0968-0896. E-ISSN 1464-3391
Grant CEP: GA ČR(CZ) GA14-00522S
Institucionální podpora: RVO:61388963
Klíčová slova: acyclic nucleoside phosphonates * open-ring * PMEO-DAPy * 5-azacytosine * PME-azaC * HPMP-5-azaC
Obor OECD: Organic chemistry
Impakt faktor: 2.881, rok: 2017

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 PME5- azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC50's of 0.15-1.12 mM 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.
Trvalý link: http://hdl.handle.net/11104/0273937