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Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility
[Image: see text] Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicycli...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770830/ https://www.ncbi.nlm.nih.gov/pubmed/33151678 http://dx.doi.org/10.1021/acs.jmedchem.0c01372 |
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author | Ang, Chee Wei Tan, Lendl Sykes, Melissa L. AbuGharbiyeh, Neda Debnath, Anjan Reid, Janet C. West, Nicholas P. Avery, Vicky M. Cooper, Matthew A. Blaskovich, Mark A. T. |
author_facet | Ang, Chee Wei Tan, Lendl Sykes, Melissa L. AbuGharbiyeh, Neda Debnath, Anjan Reid, Janet C. West, Nicholas P. Avery, Vicky M. Cooper, Matthew A. Blaskovich, Mark A. T. |
author_sort | Ang, Chee Wei |
collection | PubMed |
description | [Image: see text] Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure–activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization. |
format | Online Article Text |
id | pubmed-7770830 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-77708302020-12-29 Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility Ang, Chee Wei Tan, Lendl Sykes, Melissa L. AbuGharbiyeh, Neda Debnath, Anjan Reid, Janet C. West, Nicholas P. Avery, Vicky M. Cooper, Matthew A. Blaskovich, Mark A. T. J Med Chem [Image: see text] Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure–activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization. American Chemical Society 2020-11-05 2020-12-24 /pmc/articles/PMC7770830/ /pubmed/33151678 http://dx.doi.org/10.1021/acs.jmedchem.0c01372 Text en © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Ang, Chee Wei Tan, Lendl Sykes, Melissa L. AbuGharbiyeh, Neda Debnath, Anjan Reid, Janet C. West, Nicholas P. Avery, Vicky M. Cooper, Matthew A. Blaskovich, Mark A. T. Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility |
title | Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones
with Improved Potency and Solubility |
title_full | Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones
with Improved Potency and Solubility |
title_fullStr | Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones
with Improved Potency and Solubility |
title_full_unstemmed | Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones
with Improved Potency and Solubility |
title_short | Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones
with Improved Potency and Solubility |
title_sort | antitubercular and antiparasitic 2-nitroimidazopyrazinones
with improved potency and solubility |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770830/ https://www.ncbi.nlm.nih.gov/pubmed/33151678 http://dx.doi.org/10.1021/acs.jmedchem.0c01372 |
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