The diverse pharmacology and medicinal chemistry of phosphoramidates – a review

Oliveira, Fabrício Marques de; Barbosa, Luiz C. A.; Ismail, Fyaz M.D.

doi:10.1039/c4ra01454e

Cited by 50 publications

(35 citation statements)

References 90 publications

(140 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, increasing concern for viral infections such as HCV [100,135,176,177] and herpes virus [56] also motivates research. Because there are numerous reviews focused on prodrugs of nucleotides and nucleoside phosphonates [178–184], the following paragraphs focus primarily on other emerging applications in the nucleotide area.…”

Section: Current Applications Of Prodrug Technologymentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

153

135

View full text Add to dashboard Cite

A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

show abstract

Section: Current Applications Of Prodrug Technologymentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

153

135

View full text Add to dashboard Cite

show abstract

“…The selection of this particular type of phosphonate prodrug was based on our previous experience which led to an increase of membrane permeability and bioavailability for the antiviral ANPs. 16,18,23,24 In the first step of the one-pot reaction sequence, the cleavage of the phosphonate esters 2 and 3 with Me 3 SiBr in dry pyridine under argon atmosphere forms in situ the corresponding trimethylsilyl esters. In the second step, the reaction of these intermediates with ethyl (or isopropyl for 6j and 7j) (L)-phenylalanine in the presence of 2,2′-dithiodipyridine (Aldrithiol) and triphenylphosphine yielded the corresponding target bisamidates 6a, 6c, 6j and 7a, 7b, 7j and tetra-amidates 8h, 8i and 9h, 9i (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

“…16,17 In agreement with the literature, we have observed that the preparation of various types of prodrugs of the parent ANP-based inhibitors can significantly improve the activity in cell-based antimalarial assays. 13,15 As a prodrug of choice, we have selected compounds with a phosphoramidate linkage 18 having two identical amino acid esters attached, to facilitate entry into the cells. Due to the presence of equivalent substituents attached to the phosphorus atom, there are no difficulties associated with prodrug 4 chirality.…”

Section: Figmentioning

confidence: 99%

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Hocková

Janeba

Naesens

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors -the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC 50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads.

show abstract

“…33,34,35 In our SAR-study, the ethyl ester of the natural amino acid, L-phenylalanine, was selected to mask both phosphonate groups of our inhibitors. 36,37 This type of prodrug is more stable than ester prodrugs.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

Špaček

Keough

Chavchich³

et al. 2017

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Abstract:Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N 9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower K i values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest K i values obtained for the two parasite enzymes were 0.1 µM (Pf) and 0.2 µM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture 2 with IC 50 values of 0.8 and 1.5 µM. These two compounds exhibited low cytotoxicity in human A549 cells having CC 50 values of >300 µM resulting in an excellent selectivity index.

show abstract

The diverse pharmacology and medicinal chemistry of phosphoramidates – a review

Abstract: Promising examples of the phosphoramidates, which possess antiviral, antitumor, antibacterial, antimalarial and anti-protozoal as well as enzyme inhibitor activity are reviewed.

Cited by 50 publications

References 90 publications

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

Contact Info

Product

Resources

About