Aryl H-Phosphonates 17: (N-Aryl)phosphoramidates of Pyrimidine Nucleoside Analogues and Their Synthesis, Selected Properties, and Anti-HIV Activity

Abstract

New synthetic protocol for the preparation of nucleoside 5'-(N-aryl)phosphoramidate monoesters 4 was developed. It consisted of a condensation of the corresponding nucleoside 5'-H-phosphonates with aromatic- or heteroaromatic amines promoted by diphenyl phosphorochloridate, followed by oxidation of the produced H-phosphonamidates with iodine/water. 5'-(N-Aryl)phosphoramidate monoesters derived from 3'-azido-3'-deoxythymidine (AZT) or 2',3'-dideoxyuridine (ddU) nucleosides and various aromatic and heteroaromatic amines were evaluated as potential anti-HIV drugs. It was found that these compounds act most likely as pronucleotides and that some of them have therapeutic indices superior to those of the reference AZT.

Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2′,3′-dideoxynucleoside (N-heteroaryl)phosphoramidates of increased lipophilicity

“…Similarly as it was observed previously for 4APy (2a) [5], condensations of AZT Hphosphonate 1a with more basic amines led to poor results (Table 1, entries 6 & 10), presumably due to coincidence of several factors. The first was an undesired superfluous activation of the initially formed H-phosphonamidate esters 3 ( Fig.…”

“…Thus, tris(triazoyl)phosphoramidate 10 [15] was reacted with an amine (2) to yield monosubstituted amides of type 11. Similarly as the previously described di(triazoyl)[N-(pyridin-4-yl)]phosphoramidate 11a [5], also derivatives of 2APy (11b), 4A2MQ (11e), 1AIQ (11i), and 2AQ (11k) precipitated from the reaction mixtures and could be readily isolated as pure products (the last were unstable during storage and should be prepared directly before use). In contrast, derivatives of other, less basic heteroarylamines remained in solution and attempts to use them directly for the next reaction steps gave poor results.…”

“…One of the challenges is to overcome the AZT toxicity associated with accumulation of AZT monophosphate (AZTMP), which formed in cells rapidly from the parent nucleoside in a reaction catalyzed by thymidine kinase (TK). In contrast, phosphorylation of AZTMP to M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 The most plausible explanation of these results is formation of a mixed pyrophosphate 6 (two diastereomers), for which the multiplet at ca. - 2 ].…”

One-pot synthesis and in vivo biological evaluation of new pyrimidine privileged scaffolds as potent anti-inflammatory agents

“…They were found to be potent agents for anti-fungal [18], anti-bacterial [19], anti-inflammatory [20,21], anti-cancer [22][23][24], anti-HIV [25,26], and anti-tuberculosis activities [27,28]. The synthesized 4-hydroxy-2-methyl-6-(phenyl)pyrimidine-5-carbonitrile derivatives are also found to resemble many natural products (Fig.…”

“…To rationalize the applications of the synthesized compounds, the anti-inflammatory activity of all newly synthesized pyrimidine derivatives have been determined at 25 .. H H Scheme 2 Plausible mechanism for the formation of 4-hydroxy-2-methyl-6-(3-nitrophenyl)pyrimidine-5-carbonitrile One-pot synthesis and in vivo biological evaluation of… a standard reference drug. The effects of all synthesized compounds and standard reference drugs on paw edema induced by carrageenan are depicted in Table 3 and also by bar diagram (Fig.…”