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Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds
[Image: see text] RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923871/ https://www.ncbi.nlm.nih.gov/pubmed/20666371 http://dx.doi.org/10.1021/jm1004754 |
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author | Ruda, Gian Filippo Wong, Pui Ee Alibu, Vincent P. Norval, Suzanne Read, Kevin D. Barrett, Michael P. Gilbert, Ian H. |
author_facet | Ruda, Gian Filippo Wong, Pui Ee Alibu, Vincent P. Norval, Suzanne Read, Kevin D. Barrett, Michael P. Gilbert, Ian H. |
author_sort | Ruda, Gian Filippo |
collection | PubMed |
description | [Image: see text] RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood. |
format | Text |
id | pubmed-2923871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-29238712010-08-19 Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds Ruda, Gian Filippo Wong, Pui Ee Alibu, Vincent P. Norval, Suzanne Read, Kevin D. Barrett, Michael P. Gilbert, Ian H. J Med Chem [Image: see text] RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood. American Chemical Society 2010-07-28 2010-08-26 /pmc/articles/PMC2923871/ /pubmed/20666371 http://dx.doi.org/10.1021/jm1004754 Text en Copyright © 2010 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. |
spellingShingle | Ruda, Gian Filippo Wong, Pui Ee Alibu, Vincent P. Norval, Suzanne Read, Kevin D. Barrett, Michael P. Gilbert, Ian H. Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds |
title | Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds |
title_full | Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds |
title_fullStr | Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds |
title_full_unstemmed | Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds |
title_short | Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds |
title_sort | aryl phosphoramidates of 5-phospho erythronohydroxamic acid, a new class of potent trypanocidal compounds |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923871/ https://www.ncbi.nlm.nih.gov/pubmed/20666371 http://dx.doi.org/10.1021/jm1004754 |
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