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Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi
Chagas disease is a neglected parasitic disease caused by the parasitic protozoan Trypanosoma cruzi and currently affects around 8 million people. Previously, 2‐isopropyl‐5‐(4‐methoxy‐3‐(pyridin‐3‐yl)phenyl)‐4,4‐dimethyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one (NPD‐0227) was discovered to be a sub‐micromolar i...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496920/ https://www.ncbi.nlm.nih.gov/pubmed/32249532 http://dx.doi.org/10.1002/cmdc.202000136 |
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author | Sijm, Maarten Sterk, Geert Jan Caljon, Guy Maes, Louis de Esch, Iwan J. P. Leurs, Rob |
author_facet | Sijm, Maarten Sterk, Geert Jan Caljon, Guy Maes, Louis de Esch, Iwan J. P. Leurs, Rob |
author_sort | Sijm, Maarten |
collection | PubMed |
description | Chagas disease is a neglected parasitic disease caused by the parasitic protozoan Trypanosoma cruzi and currently affects around 8 million people. Previously, 2‐isopropyl‐5‐(4‐methoxy‐3‐(pyridin‐3‐yl)phenyl)‐4,4‐dimethyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one (NPD‐0227) was discovered to be a sub‐micromolar inhibitor (pIC(50)=6.4) of T. cruzi. So far, SAR investigations of this scaffold have focused on the alkoxy substituent, the pyrazolone nitrogen substituent and the aromatic substituent of the core phenylpyrazolone. In this study, modifications of the phenyldihydropyrazolone scaffold are described. Variations were introduced by installing different substituents on the phenyl core, modifying the geminal dimethyl and installing various bio‐isosteres of the dihydropyrazolone group. The anti T. cruzi activity of NPD‐0227 could not be surpassed as the most potent compounds show pIC(50) values of around 6.3. However, valuable additional SAR data for this interesting scaffold was obtained, and the data suggest that a scaffold hop is feasible as the pyrazolone moiety can be replaced by a oxazole or oxadiazole with minimal loss of activity. |
format | Online Article Text |
id | pubmed-7496920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74969202020-09-25 Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi Sijm, Maarten Sterk, Geert Jan Caljon, Guy Maes, Louis de Esch, Iwan J. P. Leurs, Rob ChemMedChem Full Papers Chagas disease is a neglected parasitic disease caused by the parasitic protozoan Trypanosoma cruzi and currently affects around 8 million people. Previously, 2‐isopropyl‐5‐(4‐methoxy‐3‐(pyridin‐3‐yl)phenyl)‐4,4‐dimethyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one (NPD‐0227) was discovered to be a sub‐micromolar inhibitor (pIC(50)=6.4) of T. cruzi. So far, SAR investigations of this scaffold have focused on the alkoxy substituent, the pyrazolone nitrogen substituent and the aromatic substituent of the core phenylpyrazolone. In this study, modifications of the phenyldihydropyrazolone scaffold are described. Variations were introduced by installing different substituents on the phenyl core, modifying the geminal dimethyl and installing various bio‐isosteres of the dihydropyrazolone group. The anti T. cruzi activity of NPD‐0227 could not be surpassed as the most potent compounds show pIC(50) values of around 6.3. However, valuable additional SAR data for this interesting scaffold was obtained, and the data suggest that a scaffold hop is feasible as the pyrazolone moiety can be replaced by a oxazole or oxadiazole with minimal loss of activity. John Wiley and Sons Inc. 2020-04-27 2020-07-20 /pmc/articles/PMC7496920/ /pubmed/32249532 http://dx.doi.org/10.1002/cmdc.202000136 Text en © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Full Papers Sijm, Maarten Sterk, Geert Jan Caljon, Guy Maes, Louis de Esch, Iwan J. P. Leurs, Rob Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi |
title | Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi
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title_full | Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi
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title_fullStr | Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi
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title_full_unstemmed | Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi
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title_short | Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi
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title_sort | structure‐activity relationship of phenylpyrazolones against trypanosoma cruzi |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496920/ https://www.ncbi.nlm.nih.gov/pubmed/32249532 http://dx.doi.org/10.1002/cmdc.202000136 |
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