Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity

[Image: see text] Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end...

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Autores principales: Stachulski, Andrew V., Rossignol, Jean-Francois, Pate, Sophie, Taujanskas, Joshua, Iggo, Jonathan A., Aerts, Rudi, Pascal, Etienne, Piacentini, Sara, La Frazia, Simone, Santoro, M. Gabriella, van Vooren, Lieven, Sintubin, Liesje, Cooper, Mark, Swift, Karl, O’Neill, Paul M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10436260/
https://www.ncbi.nlm.nih.gov/pubmed/37599793
http://dx.doi.org/10.1021/acsbiomedchemau.2c00083
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author Stachulski, Andrew V.
Rossignol, Jean-Francois
Pate, Sophie
Taujanskas, Joshua
Iggo, Jonathan A.
Aerts, Rudi
Pascal, Etienne
Piacentini, Sara
La Frazia, Simone
Santoro, M. Gabriella
van Vooren, Lieven
Sintubin, Liesje
Cooper, Mark
Swift, Karl
O’Neill, Paul M.
author_facet Stachulski, Andrew V.
Rossignol, Jean-Francois
Pate, Sophie
Taujanskas, Joshua
Iggo, Jonathan A.
Aerts, Rudi
Pascal, Etienne
Piacentini, Sara
La Frazia, Simone
Santoro, M. Gabriella
van Vooren, Lieven
Sintubin, Liesje
Cooper, Mark
Swift, Karl
O’Neill, Paul M.
author_sort Stachulski, Andrew V.
collection PubMed
description [Image: see text] Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end products of the degradation were peptides formed by rearrangement. These peptides were stable solids: they maintained significant antiviral activity, and in general, they showed improved pharmacokinetics (better solubility and reduced clearance) compared to the parent thiazolides. We describe the preparation and evaluation of these peptides.
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spelling pubmed-104362602023-08-19 Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity Stachulski, Andrew V. Rossignol, Jean-Francois Pate, Sophie Taujanskas, Joshua Iggo, Jonathan A. Aerts, Rudi Pascal, Etienne Piacentini, Sara La Frazia, Simone Santoro, M. Gabriella van Vooren, Lieven Sintubin, Liesje Cooper, Mark Swift, Karl O’Neill, Paul M. ACS Bio Med Chem Au [Image: see text] Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end products of the degradation were peptides formed by rearrangement. These peptides were stable solids: they maintained significant antiviral activity, and in general, they showed improved pharmacokinetics (better solubility and reduced clearance) compared to the parent thiazolides. We describe the preparation and evaluation of these peptides. American Chemical Society 2023-04-11 /pmc/articles/PMC10436260/ /pubmed/37599793 http://dx.doi.org/10.1021/acsbiomedchemau.2c00083 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Stachulski, Andrew V.
Rossignol, Jean-Francois
Pate, Sophie
Taujanskas, Joshua
Iggo, Jonathan A.
Aerts, Rudi
Pascal, Etienne
Piacentini, Sara
La Frazia, Simone
Santoro, M. Gabriella
van Vooren, Lieven
Sintubin, Liesje
Cooper, Mark
Swift, Karl
O’Neill, Paul M.
Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity
title Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity
title_full Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity
title_fullStr Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity
title_full_unstemmed Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity
title_short Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity
title_sort thiazolide prodrug esters and derived peptides: synthesis and activity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10436260/
https://www.ncbi.nlm.nih.gov/pubmed/37599793
http://dx.doi.org/10.1021/acsbiomedchemau.2c00083
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