ChloroquineV1, Istex, Corpus, bibRecord, 000927

Similar Structure−Activity Relationships of Quinoline Derivatives for Antiprion and Antimalarial Effects

Identifieur interne : 000927 ( Istex/Corpus ); précédent : 000926; suivant : 000928

Similar Structure−Activity Relationships of Quinoline Derivatives for Antiprion and Antimalarial Effects

Auteurs : Ralf Klingenstein ; Patricia Melnyk ; S. Rutger Leliveld ; Adina Ryckebusch ; Carsten Korth

Source :

Journal of Medicinal Chemistry [ 0022-2623 ] ; 2006.

RBID : ISTEX:5EFE8F7BFB49F223533A60B276110A273E50F8C3

Abstract

Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrPSc, a pathogenic misfolded isoform of the normal cellular prion protein (PrPC). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure−activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.

Url:

https://api.istex.fr/ark:/67375/TPS-K3RN8GHW-G/fulltext.pdf

DOI: 10.1021/jm0602763

Links to Exploration step

ISTEX:5EFE8F7BFB49F223533A60B276110A273E50F8C3

Le document en format XML

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<author xml:id="author-0003"><persName><surname>Ryckebusch</surname>
<forename type="first">Adina</forename>
</persName>
<affiliation>Institute for Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany, and
UMR CNRS 8161, Universités Lille 2 et Lille 1, IBL, IPL, 1 rue du Pr Calmette, B.P. 245, 59021 Lille Cedex, France
</affiliation>
<note place="foot"><ref>‡</ref>
<p>
 UMR CNRS 8161.</p>
</note>
<note place="foot"><ref>§</ref>
<p>
 Present address: UMR CNRS 8009, Université des Sciences et
Technologies de Lille Bât. C6-59655 Villeneuve d’Ascq Cedex, France.</p>
</note>
</author>
<author xml:id="author-0004" role="corresp"><persName><surname>Korth</surname>
<forename type="first">Carsten</forename>
</persName>
<affiliation>Institute for Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany, and
UMR CNRS 8161, Universités Lille 2 et Lille 1, IBL, IPL, 1 rue du Pr Calmette, B.P. 245, 59021 Lille Cedex, France
</affiliation>
<note place="foot"><ref>†</ref>
<p>
 Heinrich Heine University Düsseldorf.</p>
</note>
<affiliation role="corresp"> To whom correspondence should be addressed. Tel:  +49-211 811 6153. Fax:  +49-211-811 7804. E-mail:  ckorth@uni-duesseldorf.de.</affiliation>
</author>
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<p>Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of
PrP<hi rend="superscript">Sc</hi>
, a pathogenic misfolded isoform of the normal cellular prion protein (PrP<hi rend="superscript">C</hi>). Until now, no
pharmacological options exist for these novel pathogens. Here we describe the screening of a series of
polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently
prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The
most active molecule, named <hi rend="bold">42</hi>
, had a half-effective concentration (EC<hi rend="subscript">50</hi>) for antiprion activity of 50 nM.
In a library of quinoline derivatives we were able to identify several structure−activity relationships (SAR).
Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria,
particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion
and antimalarial substances overlap.
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<title-group><article-title>Similar Structure−Activity Relationships of Quinoline Derivatives for Antiprion and
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<contrib-group><contrib contrib-type="author"><name><surname>Klingenstein</surname>
<given-names>Ralf</given-names>
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<xref rid="jm0602763AF2">†</xref>
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<contrib contrib-type="author"><name><surname>Melnyk</surname>
<given-names>Patricia</given-names>
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<xref rid="jm0602763AF3">‡</xref>
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<contrib contrib-type="author"><name><surname>Leliveld</surname>
<given-names>S. Rutger</given-names>
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<xref rid="jm0602763AF2">†</xref>
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<contrib contrib-type="author"><name><surname>Ryckebusch</surname>
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<xref rid="jm0602763AF3">‡</xref>
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<aff>Institute for Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany, and
UMR CNRS 8161, Universités Lille 2 et Lille 1, IBL, IPL, 1 rue du Pr Calmette, B.P. 245, 59021 Lille Cedex, France
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 Heinrich Heine University Düsseldorf.</p>
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<p>
 UMR CNRS 8161.</p>
</fn>
<fn id="jm0602763AF4"><label>§</label>
<p>
 Present address: UMR CNRS 8009, Université des Sciences et
Technologies de Lille Bât. C6-59655 Villeneuve d’Ascq Cedex, France.</p>
</fn>
<corresp id="jm0602763AF1">
 To whom correspondence should be addressed. Tel:  +49-211 811
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<p>Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of
PrP<sup>Sc</sup>
, a pathogenic misfolded isoform of the normal cellular prion protein (PrP<sup>C</sup>). Until now, no
pharmacological options exist for these novel pathogens. Here we describe the screening of a series of
polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently
prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The
most active molecule, named <bold>42</bold>
, had a half-effective concentration (EC<sub>50</sub>) for antiprion activity of 50 nM.
In a library of quinoline derivatives we were able to identify several structure−activity relationships (SAR).
Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria,
particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion
and antimalarial substances overlap.
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Similar Structure−Activity Relationships of Quinoline Derivatives for Antiprion and Antimalarial Effects

Similar Structure−Activity Relationships of Quinoline Derivatives for Antiprion and Antimalarial Effects

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