SrasV1, Main, Exploration, bibRecord, 000D34

Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Identifieur interne : 000D34 ( Main/Exploration ); précédent : 000D33; suivant : 000D35

Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Auteurs : Justine Desroches [France] ; Charline Kieffer [France] ; Nicolas Primas [France] ; Sébastien Hutter [France] ; Armand Gellis [France] ; Hussein El-Kashef [Égypte] ; Pascal Rathelot [France] ; Pierre Verhaeghe [France] ; Nadine Azas [France] ; Patrice Vanelle [France]

Source :

European Journal of Medicinal Chemistry [ 0223-5234 ] ; 2017.

RBID : Hal:hal-01416990

English descriptors

mix :
- In vitro HepG2 cytotoxicity, In vitro antiplasmodial activity, Plasmodium falciparum, Quinoline, Quinoxaline, Structure-Activity Relationships., Thienopyrimidine, Trichloromethyl goup, Quinazoline.

Abstract

From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I – V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active asandless cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC50 = 0.4 μM, selectivity index = 100), but also highlighted an active (IC50 = 0.4 μM) and quite selective (SI = 265) synthesis intermediate.

Url:

https://hal.archives-ouvertes.fr/hal-01416990

DOI: 10.1016/j.ejmech.2016.09.029

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Hal, to step Corpus: 000047
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to stream Main, to step Merge: 000D36
to stream Main, to step Curation: 000D34

Le document en format XML

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<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
<orgName type="university">Université d'Aix-Marseille</orgName>
</affiliation>
</author>
<author><name sortKey="Vanelle, Patrice" sort="Vanelle, Patrice" uniqKey="Vanelle P" first="Patrice" last="Vanelle">Patrice Vanelle</name>
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          <orgName>Institut de Chimie Radicalaire</orgName>
          <orgName type="acronym">ICR</orgName>
          <date type="start">2012</date>
          <desc>            <address>              <addrLine>Avenue Escadrille Normandie-Niemen Service D42 13397 Marseille cedex 20</addrLine>
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          <orgName>Aix Marseille Université</orgName>
          <orgName type="acronym">AMU</orgName>
          <date type="start">2012-01-01</date>
          <desc>            <address>              <addrLine>Aix-Marseille UniversitéJardins du Pharo58 Boulevard Charles Livon13284 Marseille cedex 7</addrLine>
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            </address>
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          <date type="start">1939-10-19</date>
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            </address>
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          </desc>
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</hal:affiliation>
<country>France</country>
<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
<orgName type="university">Université d'Aix-Marseille</orgName>
</affiliation>
</author>
</analytic>
<idno type="DOI">10.1016/j.ejmech.2016.09.029</idno>
<series><title level="j">European Journal of Medicinal Chemistry</title>
<idno type="ISSN">0223-5234</idno>
<imprint><date type="datePub">2017</date>
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<profileDesc><textClass><keywords scheme="mix" xml:lang="en"><term> In vitro HepG2 cytotoxicity</term>
<term> In vitro antiplasmodial activity</term>
<term> Plasmodium falciparum</term>
<term> Quinoline</term>
<term> Quinoxaline</term>
<term> Structure-Activity Relationships.</term>
<term> Thienopyrimidine</term>
<term> Trichloromethyl goup</term>
<term>Quinazoline</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">              <p>From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I – V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active asandless cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC50 = 0.4 μM, selectivity index = 100), but also highlighted an active (IC50 = 0.4 μM) and quite selective (SI = 265) synthesis intermediate.</p>
            </div>
</front>
</TEI>
<affiliations><list><country><li>France</li>
<li>Égypte</li>
</country>
<region><li>Provence-Alpes-Côte d'Azur</li>
</region>
<settlement><li>Marseille</li>
</settlement>
<orgName><li>Université d'Aix-Marseille</li>
</orgName>
</list>
<tree><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Desroches, Justine" sort="Desroches, Justine" uniqKey="Desroches J" first="Justine" last="Desroches">Justine Desroches</name>
</region>
<name sortKey="Azas, Nadine" sort="Azas, Nadine" uniqKey="Azas N" first="Nadine" last="Azas">Nadine Azas</name>
<name sortKey="Gellis, Armand" sort="Gellis, Armand" uniqKey="Gellis A" first="Armand" last="Gellis">Armand Gellis</name>
<name sortKey="Hutter, Sebastien" sort="Hutter, Sebastien" uniqKey="Hutter S" first="Sébastien" last="Hutter">Sébastien Hutter</name>
<name sortKey="Kieffer, Charline" sort="Kieffer, Charline" uniqKey="Kieffer C" first="Charline" last="Kieffer">Charline Kieffer</name>
<name sortKey="Primas, Nicolas" sort="Primas, Nicolas" uniqKey="Primas N" first="Nicolas" last="Primas">Nicolas Primas</name>
<name sortKey="Rathelot, Pascal" sort="Rathelot, Pascal" uniqKey="Rathelot P" first="Pascal" last="Rathelot">Pascal Rathelot</name>
<name sortKey="Vanelle, Patrice" sort="Vanelle, Patrice" uniqKey="Vanelle P" first="Patrice" last="Vanelle">Patrice Vanelle</name>
<name sortKey="Verhaeghe, Pierre" sort="Verhaeghe, Pierre" uniqKey="Verhaeghe P" first="Pierre" last="Verhaeghe">Pierre Verhaeghe</name>
</country>
<country name="Égypte"><noRegion><name sortKey="El Kashef, Hussein" sort="El Kashef, Hussein" uniqKey="El Kashef H" first="Hussein" last="El-Kashef">Hussein El-Kashef</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

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