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 EC'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.

Recent Advances on the s‐Triazine Scaffold with Emphasis on Synthesis, Structure‐Activity and Pharmacological Aspects: A Concise Review

“…Krecmerová and co‐worker in 2017, stated the synthesis and anti‐viral activity of some acyclic nucleoside phosphonates ( 112 ) [5] . Anti‐viral and cytotoxicity properties of the synthesized compounds were studied, and one of the compounds 112 (Figure 13), came out as highly active and selective PME‐5‐azaC (1‐[2‐(phosphonomethoxy) ethyl]‐5‐azacytosine) prodrug against Varicella zoster virus, Herpes simplex virus and Human cytomegalovirus with EC 50 values ranging 0.15–1.12 mM.…”

“…The symmetrical shape of the s ‐triazine is one of the major reasons responsible for its excellent biological profile. The s ‐triazine ring provides exceptional framework for the design of biologically potent molecules with broad clinical variabilities like anti‐protozoa, [3] anti‐cancer, [4] anti‐viral, [5] anti‐microbial [6] and many more as summarized in Figure 2. It is also the basic structure of some herbicides like amitole, atrazine, cyanazine, simazine, trietazine, and resin modifiers like melamine and benzoguanamine [7] .…”

COVID-19 therapy: What weapons do we bring into battle?

“…From the pharmacologic perspective, nitrogenous bases are investigated as pharmacophores and are found in the structure of many drugs and experimental substances with various activities, 85 such as antitumoral, 86 antibacterial, 87 antiparasitic, 88 and antiviral. 89 , 90

Fig. 3 Chemical structures of pyrimidine nitrogenous bases cytosine (5), uracil (6) and thymine (7) and pyrimidine derivatives drugs: 5-Fluorouracil (8) ; Gemcitabine (9) ; Baricitinib (10) ; Sunitinib ( 11 ); Erlotinib (12); Galidesivir ( 13 ); Sofosbuvir ( 14 ); Telbivudine ( 15 ).

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“…This format solves issues of high polarity in its final structure prompted by the phosphonic acid, which interferes with pharmacological properties and causes low cellular permeability and low oral bioavailability. 90 …”

Novel camphor-based pyrimidine derivatives induced cancer cell death through a ROS-mediated mitochondrial apoptosis pathway

“…9 The majority of the commercially available drugs are built on heterocyclic scaffolds and these chemical fragments are responsible for desired pharmacological activity. 10 Pyrimidine, a six membered heterocyclic ring with nitrogen atom, exhibits various pharmacological activities such as anticancer, [11][12][13] antimicrobial, 14,15 antiviral, [16][17][18] anti-tubercular, 19,20 anti-inammatory, 21,22 antimalarial, 23,24 anti-diabetic 25 and antipyretic. 26 Among these diverse pyrimidine derivatives, amino-pyrimidine plays a vital role in the therapeutic activities against cancers, meanwhile, a large number of studies have been reported in recent years.…”