Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines

Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels...

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Autores principales: Large, Jonathan M., Birchall, Kristian, Bouloc, Nathalie S., Merritt, Andy T., Smiljanic-Hurley, Ela, Tsagris, Denise J., Wheldon, Mary C., Ansell, Keith H., Coombs, Peter J., Kettleborough, Catherine A., Whalley, David, Stewart, Lindsay B., Bowyer, Paul W., Baker, David A., Osborne, Simon A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355318/
https://www.ncbi.nlm.nih.gov/pubmed/30553738
http://dx.doi.org/10.1016/j.bmcl.2018.11.039
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author Large, Jonathan M.
Birchall, Kristian
Bouloc, Nathalie S.
Merritt, Andy T.
Smiljanic-Hurley, Ela
Tsagris, Denise J.
Wheldon, Mary C.
Ansell, Keith H.
Coombs, Peter J.
Kettleborough, Catherine A.
Whalley, David
Stewart, Lindsay B.
Bowyer, Paul W.
Baker, David A.
Osborne, Simon A.
author_facet Large, Jonathan M.
Birchall, Kristian
Bouloc, Nathalie S.
Merritt, Andy T.
Smiljanic-Hurley, Ela
Tsagris, Denise J.
Wheldon, Mary C.
Ansell, Keith H.
Coombs, Peter J.
Kettleborough, Catherine A.
Whalley, David
Stewart, Lindsay B.
Bowyer, Paul W.
Baker, David A.
Osborne, Simon A.
author_sort Large, Jonathan M.
collection PubMed
description Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles.
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spelling pubmed-63553182019-02-08 Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines Large, Jonathan M. Birchall, Kristian Bouloc, Nathalie S. Merritt, Andy T. Smiljanic-Hurley, Ela Tsagris, Denise J. Wheldon, Mary C. Ansell, Keith H. Coombs, Peter J. Kettleborough, Catherine A. Whalley, David Stewart, Lindsay B. Bowyer, Paul W. Baker, David A. Osborne, Simon A. Bioorg Med Chem Lett Article Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles. Elsevier Science Ltd 2019-02-01 /pmc/articles/PMC6355318/ /pubmed/30553738 http://dx.doi.org/10.1016/j.bmcl.2018.11.039 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Large, Jonathan M.
Birchall, Kristian
Bouloc, Nathalie S.
Merritt, Andy T.
Smiljanic-Hurley, Ela
Tsagris, Denise J.
Wheldon, Mary C.
Ansell, Keith H.
Coombs, Peter J.
Kettleborough, Catherine A.
Whalley, David
Stewart, Lindsay B.
Bowyer, Paul W.
Baker, David A.
Osborne, Simon A.
Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines
title Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines
title_full Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines
title_fullStr Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines
title_full_unstemmed Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines
title_short Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines
title_sort potent inhibitors of malarial p. falciparum protein kinase g: improving the cell activity of a series of imidazopyridines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355318/
https://www.ncbi.nlm.nih.gov/pubmed/30553738
http://dx.doi.org/10.1016/j.bmcl.2018.11.039
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