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Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives
The rise of antimicrobial resistance poses a severe threat to public health. The natural product chlorotonil was identified as a new antibiotic targeting multidrug resistant Gram‐positive pathogens and Plasmodium falciparum. Although chlorotonil shows promising activities, the scaffold is highly lip...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9400904/ https://www.ncbi.nlm.nih.gov/pubmed/35485800 http://dx.doi.org/10.1002/anie.202202816 |
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author | Hofer, Walter Oueis, Emilia Fayad, Antoine Abou Deschner, Felix Andreas, Anastasia de Carvalho, Laìs Pessanha Hüttel, Stephan Bernecker, Steffen Pätzold, Linda Morgenstern, Bernd Zaburannyi, Nestor Bischoff, Markus Stadler, Marc Held, Jana Herrmann, Jennifer Müller, Rolf |
author_facet | Hofer, Walter Oueis, Emilia Fayad, Antoine Abou Deschner, Felix Andreas, Anastasia de Carvalho, Laìs Pessanha Hüttel, Stephan Bernecker, Steffen Pätzold, Linda Morgenstern, Bernd Zaburannyi, Nestor Bischoff, Markus Stadler, Marc Held, Jana Herrmann, Jennifer Müller, Rolf |
author_sort | Hofer, Walter |
collection | PubMed |
description | The rise of antimicrobial resistance poses a severe threat to public health. The natural product chlorotonil was identified as a new antibiotic targeting multidrug resistant Gram‐positive pathogens and Plasmodium falciparum. Although chlorotonil shows promising activities, the scaffold is highly lipophilic and displays potential biological instabilities. Therefore, we strived towards improving its pharmaceutical properties by semisynthesis. We demonstrated stereoselective epoxidation of chlorotonils and epoxide ring opening in moderate to good yields providing derivatives with significantly enhanced solubility. Furthermore, in vivo stability of the derivatives was improved while retaining their nanomolar activity against critical human pathogens (e.g. methicillin‐resistant Staphylococcus aureus and P. falciparum). Intriguingly, we showed further superb activity for the frontrunner molecule in a mouse model of S. aureus infection. |
format | Online Article Text |
id | pubmed-9400904 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94009042022-08-26 Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives Hofer, Walter Oueis, Emilia Fayad, Antoine Abou Deschner, Felix Andreas, Anastasia de Carvalho, Laìs Pessanha Hüttel, Stephan Bernecker, Steffen Pätzold, Linda Morgenstern, Bernd Zaburannyi, Nestor Bischoff, Markus Stadler, Marc Held, Jana Herrmann, Jennifer Müller, Rolf Angew Chem Int Ed Engl Research Articles The rise of antimicrobial resistance poses a severe threat to public health. The natural product chlorotonil was identified as a new antibiotic targeting multidrug resistant Gram‐positive pathogens and Plasmodium falciparum. Although chlorotonil shows promising activities, the scaffold is highly lipophilic and displays potential biological instabilities. Therefore, we strived towards improving its pharmaceutical properties by semisynthesis. We demonstrated stereoselective epoxidation of chlorotonils and epoxide ring opening in moderate to good yields providing derivatives with significantly enhanced solubility. Furthermore, in vivo stability of the derivatives was improved while retaining their nanomolar activity against critical human pathogens (e.g. methicillin‐resistant Staphylococcus aureus and P. falciparum). Intriguingly, we showed further superb activity for the frontrunner molecule in a mouse model of S. aureus infection. John Wiley and Sons Inc. 2022-06-13 2022-07-25 /pmc/articles/PMC9400904/ /pubmed/35485800 http://dx.doi.org/10.1002/anie.202202816 Text en © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Hofer, Walter Oueis, Emilia Fayad, Antoine Abou Deschner, Felix Andreas, Anastasia de Carvalho, Laìs Pessanha Hüttel, Stephan Bernecker, Steffen Pätzold, Linda Morgenstern, Bernd Zaburannyi, Nestor Bischoff, Markus Stadler, Marc Held, Jana Herrmann, Jennifer Müller, Rolf Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives |
title | Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives |
title_full | Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives |
title_fullStr | Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives |
title_full_unstemmed | Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives |
title_short | Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives |
title_sort | regio‐ and stereoselective epoxidation and acidic epoxide opening of antibacterial and antiplasmodial chlorotonils yield highly potent derivatives |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9400904/ https://www.ncbi.nlm.nih.gov/pubmed/35485800 http://dx.doi.org/10.1002/anie.202202816 |
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