Phosphoroamidate derivatives of N,O-nucleosides as inhibitors of reverse transcriptase

Abstract

Phosphoroamidate derivatives of adenine and 5-fluorouracil N,O-nucleoside analogues have been synthesized as potential antiviral prodrugs. In particular, dimethoxyphenyl phosphates, linked via nitrogen to L-leucine methyl ester were studied. The synthesized compounds were also subjected to in vitro evaluation for their RT inhibition. Results show that phosphoroamidate derivatives, in comparison with their corresponding N,O-nucleosides, present a promising antiviral activity, though of micro-molar order.

The diverse pharmacology and medicinal chemistry of phosphoramidates – a review

“…33 Recently some investigators have evaluated phosphoramidate groups covalently linked to nucleosides, a strategy known as 'phosphoramidate protide'. [12][13][14]16,19,20,24,26,31,[34][35][36][37][38] This approach was introduced by McGuigan et al (1992) as a means of improving the therapeutic potential of a prototype drug. 23 The introduction of this group favors the phosphorylation process in vivo, by converting the nucleosides into their active forms as triphosphates derivatives, commonly known as nucleotides.…”

“…Stavudine (d4T), an analogue of thymidine, is the fourth antiretroviral drug to achieve world-wide commercialization. 41 In 2011, Román et al synthesized several diasteroisomericaly pure derivatives of d4T phosphoramidates (34)(35)(36)(37). Antiviral activities against HIV-1 and HIV-2 were evaluated and the corresponding EC 50 against type HIV-1 (IIIB) are shown in Fig.…”

“…Several other research groups are also engaged in the search for promising bioactive phosphorylated molecules but have only achieved sporadic success. 13,14,16,25,29,31,[36][37][38]43,[45][46][47]…”

Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols

“…They observed moderate to high diastereoselectivities for 1,3-dipolar cycloadditions and for nucleophilic additions. Successful applications of these easily removable auxiliaries in the syntheses of biologically active agents were also reported [ 26 – 31 ]. Apart from the obvious reactivity of N -glycosyl nitrones of type 1 leading to five-membered heterocycles A or to N , N -disubstituted hydroxylamine derivatives B , a twofold nucleophilic addition of an excess of organometallic reagents furnishing compounds of type C (Nu 1 = Nu 2 ) was described and discussed by Goti et al ( Scheme 1 ) [ 32 ].…”