AustralieFrV1, Main, Exploration, bibRecord, 001354

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.

Identifieur interne : 001354 ( Main/Exploration ); précédent : 001353; suivant : 001355

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.

Auteurs : Laurent Sevaille [France] ; Laurent Gavara [France] ; Carine Bebrone [Belgique] ; Filomena De Luca [Italie] ; Lionel Nauton [France] ; Maud Achard [Allemagne] ; Paola Mercuri [Belgique] ; Silvia Tanfoni [Italie] ; Luisa Borgianni [Italie] ; Carole Guyon [France] ; Pauline Lonjon [France] ; Gülhan Turan-Zitouni [Turquie] ; Julia Dzieciolowski [Allemagne] ; Katja Becker [Allemagne] ; Lionel Bénard [France] ; Ciaran Condon [France] ; Ludovic Maillard [France] ; Jean Martinez [France] ; Jean-Marie Frère [Belgique] ; Otto Dideberg [France] ; Moreno Galleni [Belgique] ; Jean-Denis Docquier [Italie] ; Jean-François Hernandez [France]

Source :

ChemMedChem [ 1860-7187 ] ; 2017.

RBID : pubmed:28505394

Descripteurs français

KwdFr :
- Aeromonas hydrophila (enzymologie), Inhibiteurs des bêta-lactamases (), Inhibiteurs des bêta-lactamases (pharmacologie), Inhibiteurs des bêta-lactamases (synthèse chimique), Relation dose-effet des médicaments, Relation structure-activité, Stenotrophomonas maltophilia (enzymologie), Structure moléculaire, Thiones (), Thiones (pharmacologie), Thiones (synthèse chimique), Triazoles (), Triazoles (pharmacologie), Triazoles (synthèse chimique), bêta-Lactamases (métabolisme).
MESH :
- enzymologie : Aeromonas hydrophila, Stenotrophomonas maltophilia.
- métabolisme : bêta-Lactamases.
- pharmacologie : Inhibiteurs des bêta-lactamases, Thiones, Triazoles.
- synthèse chimique : Inhibiteurs des bêta-lactamases, Thiones, Triazoles.
- Inhibiteurs des bêta-lactamases, Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire, Thiones, Triazoles.

English descriptors

KwdEn :
- Aeromonas hydrophila (enzymology), Dose-Response Relationship, Drug, Molecular Structure, Stenotrophomonas maltophilia (enzymology), Structure-Activity Relationship, Thiones (chemical synthesis), Thiones (chemistry), Thiones (pharmacology), Triazoles (chemical synthesis), Triazoles (chemistry), Triazoles (pharmacology), beta-Lactamase Inhibitors (chemical synthesis), beta-Lactamase Inhibitors (chemistry), beta-Lactamase Inhibitors (pharmacology), beta-Lactamases (metabolism).
MESH :
- chemical , chemical synthesis : Thiones, Triazoles, beta-Lactamase Inhibitors.
- chemical , chemistry : Thiones, Triazoles, beta-Lactamase Inhibitors.
- enzymology : Aeromonas hydrophila, Stenotrophomonas maltophilia.
- chemical , metabolism : beta-Lactamases.
- chemical , pharmacology : Thiones, Triazoles, beta-Lactamase Inhibitors.
- Dose-Response Relationship, Drug, Molecular Structure, Structure-Activity Relationship.

Abstract

Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.

DOI: 10.1002/cmdc.201700186
PubMed: 28505394

Affiliations:

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en">1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.</title>
<author><name sortKey="Sevaille, Laurent" sort="Sevaille, Laurent" uniqKey="Sevaille L" first="Laurent" last="Sevaille">Laurent Sevaille</name>
<affiliation wicri:level="1"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5</wicri:regionArea>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Gavara, Laurent" sort="Gavara, Laurent" uniqKey="Gavara L" first="Laurent" last="Gavara">Laurent Gavara</name>
<affiliation wicri:level="1"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5</wicri:regionArea>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bebrone, Carine" sort="Bebrone, Carine" uniqKey="Bebrone C" first="Carine" last="Bebrone">Carine Bebrone</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège</wicri:regionArea>
<orgName type="university">Université de Liège</orgName>
<placeName><settlement type="city">Liège</settlement>
<region type="region" nuts="1">Région wallonne</region>
<region type="province" nuts="1">Province de Liège</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="De Luca, Filomena" sort="De Luca, Filomena" uniqKey="De Luca F" first="Filomena" last="De Luca">Filomena De Luca</name>
<affiliation wicri:level="1"><nlm:affiliation>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena</wicri:regionArea>
<wicri:noRegion>Siena</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Nauton, Lionel" sort="Nauton, Lionel" uniqKey="Nauton L" first="Lionel" last="Nauton">Lionel Nauton</name>
<affiliation wicri:level="4"><nlm:affiliation>Institut de Biologie Structurale-Jean-Pierre Ebel, UMR5075 CNRS, CEA, Université Joseph Fourier, 41 rue Jules Horowitz, 38027, Grenoble cedex 1, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut de Biologie Structurale-Jean-Pierre Ebel, UMR5075 CNRS, CEA, Université Joseph Fourier, 41 rue Jules Horowitz, 38027, Grenoble cedex 1</wicri:regionArea>
<wicri:noRegion>38027, Grenoble cedex 1</wicri:noRegion>
<orgName type="university">Université Joseph Fourier</orgName>
<placeName><settlement type="city">Grenoble</settlement>
<region type="region" nuts="2">Auvergne-Rhône-Alpes</region>
<region type="old region" nuts="2">Rhône-Alpes</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Achard, Maud" sort="Achard, Maud" uniqKey="Achard M" first="Maud" last="Achard">Maud Achard</name>
<affiliation wicri:level="3"><nlm:affiliation>EMBL Outstation c/o DESY, Notkestrasse 85, 22603, Hamburg, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>EMBL Outstation c/o DESY, Notkestrasse 85, 22603, Hamburg</wicri:regionArea>
<placeName><settlement type="city">Hambourg</settlement>
<region type="land" nuts="2">Hambourg</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mercuri, Paola" sort="Mercuri, Paola" uniqKey="Mercuri P" first="Paola" last="Mercuri">Paola Mercuri</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège</wicri:regionArea>
<orgName type="university">Université de Liège</orgName>
<placeName><settlement type="city">Liège</settlement>
<region type="region" nuts="1">Région wallonne</region>
<region type="province" nuts="1">Province de Liège</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tanfoni, Silvia" sort="Tanfoni, Silvia" uniqKey="Tanfoni S" first="Silvia" last="Tanfoni">Silvia Tanfoni</name>
<affiliation wicri:level="1"><nlm:affiliation>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena</wicri:regionArea>
<wicri:noRegion>Siena</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Borgianni, Luisa" sort="Borgianni, Luisa" uniqKey="Borgianni L" first="Luisa" last="Borgianni">Luisa Borgianni</name>
<affiliation wicri:level="1"><nlm:affiliation>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena</wicri:regionArea>
<wicri:noRegion>Siena</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Guyon, Carole" sort="Guyon, Carole" uniqKey="Guyon C" first="Carole" last="Guyon">Carole Guyon</name>
<affiliation wicri:level="1"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5</wicri:regionArea>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lonjon, Pauline" sort="Lonjon, Pauline" uniqKey="Lonjon P" first="Pauline" last="Lonjon">Pauline Lonjon</name>
<affiliation wicri:level="1"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5</wicri:regionArea>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Turan Zitouni, Gulhan" sort="Turan Zitouni, Gulhan" uniqKey="Turan Zitouni G" first="Gülhan" last="Turan-Zitouni">Gülhan Turan-Zitouni</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry, Anadolu University, Faculty of Pharmacy, 26470, Eskisehir, Turkey.</nlm:affiliation>
<country xml:lang="fr">Turquie</country>
<wicri:regionArea>Department of Pharmaceutical Chemistry, Anadolu University, Faculty of Pharmacy, 26470, Eskisehir</wicri:regionArea>
<wicri:noRegion>Eskisehir</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Dzieciolowski, Julia" sort="Dzieciolowski, Julia" uniqKey="Dzieciolowski J" first="Julia" last="Dzieciolowski">Julia Dzieciolowski</name>
<affiliation wicri:level="1"><nlm:affiliation>Chair of Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Chair of Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Heinrich-Buff-Ring 26-32, 35392, Giessen</wicri:regionArea>
<wicri:noRegion>35392, Giessen</wicri:noRegion>
<wicri:noRegion>35392, Giessen</wicri:noRegion>
<wicri:noRegion>Giessen</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Becker, Katja" sort="Becker, Katja" uniqKey="Becker K" first="Katja" last="Becker">Katja Becker</name>
<affiliation wicri:level="1"><nlm:affiliation>Chair of Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Chair of Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Heinrich-Buff-Ring 26-32, 35392, Giessen</wicri:regionArea>
<wicri:noRegion>35392, Giessen</wicri:noRegion>
<wicri:noRegion>35392, Giessen</wicri:noRegion>
<wicri:noRegion>Giessen</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Benard, Lionel" sort="Benard, Lionel" uniqKey="Benard L" first="Lionel" last="Bénard">Lionel Bénard</name>
<affiliation wicri:level="4"><nlm:affiliation>UMR8226, CNRS, Université Pierre et Marie Curie, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>UMR8226, CNRS, Université Pierre et Marie Curie, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Pierre-et-Marie-Curie</orgName>
</affiliation>
</author>
<author><name sortKey="Condon, Ciaran" sort="Condon, Ciaran" uniqKey="Condon C" first="Ciaran" last="Condon">Ciaran Condon</name>
<affiliation wicri:level="3"><nlm:affiliation>UMR8261, CNRS, Université Paris-Diderot, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>UMR8261, CNRS, Université Paris-Diderot, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Maillard, Ludovic" sort="Maillard, Ludovic" uniqKey="Maillard L" first="Ludovic" last="Maillard">Ludovic Maillard</name>
<affiliation wicri:level="3"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5</wicri:regionArea>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
<placeName><region type="region" nuts="2">Occitanie (région administrative)</region>
<region type="old region" nuts="2">Languedoc-Roussillon</region>
<settlement type="city">Montpellier</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martinez, Jean" sort="Martinez, Jean" uniqKey="Martinez J" first="Jean" last="Martinez">Jean Martinez</name>
<affiliation wicri:level="3"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5</wicri:regionArea>
<placeName><region type="region" nuts="2">Occitanie (région administrative)</region>
<region type="old region" nuts="2">Languedoc-Roussillon</region>
<settlement type="city">Montpellier</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Frere, Jean Marie" sort="Frere, Jean Marie" uniqKey="Frere J" first="Jean-Marie" last="Frère">Jean-Marie Frère</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège</wicri:regionArea>
<orgName type="university">Université de Liège</orgName>
<placeName><settlement type="city">Liège</settlement>
<region type="region" nuts="1">Région wallonne</region>
<region type="province" nuts="1">Province de Liège</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dideberg, Otto" sort="Dideberg, Otto" uniqKey="Dideberg O" first="Otto" last="Dideberg">Otto Dideberg</name>
<affiliation wicri:level="4"><nlm:affiliation>Institut de Biologie Structurale-Jean-Pierre Ebel, UMR5075 CNRS, CEA, Université Joseph Fourier, 41 rue Jules Horowitz, 38027, Grenoble cedex 1, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut de Biologie Structurale-Jean-Pierre Ebel, UMR5075 CNRS, CEA, Université Joseph Fourier, 41 rue Jules Horowitz, 38027, Grenoble cedex 1</wicri:regionArea>
<wicri:noRegion>38027, Grenoble cedex 1</wicri:noRegion>
<orgName type="university">Université Joseph Fourier</orgName>
<placeName><settlement type="city">Grenoble</settlement>
<region type="region" nuts="2">Auvergne-Rhône-Alpes</region>
<region type="old region" nuts="2">Rhône-Alpes</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Galleni, Moreno" sort="Galleni, Moreno" uniqKey="Galleni M" first="Moreno" last="Galleni">Moreno Galleni</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège</wicri:regionArea>
<orgName type="university">Université de Liège</orgName>
<placeName><settlement type="city">Liège</settlement>
<region type="region" nuts="1">Région wallonne</region>
<region type="province" nuts="1">Province de Liège</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Docquier, Jean Denis" sort="Docquier, Jean Denis" uniqKey="Docquier J" first="Jean-Denis" last="Docquier">Jean-Denis Docquier</name>
<affiliation wicri:level="1"><nlm:affiliation>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena</wicri:regionArea>
<wicri:noRegion>Siena</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hernandez, Jean Francois" sort="Hernandez, Jean Francois" uniqKey="Hernandez J" first="Jean-François" last="Hernandez">Jean-François Hernandez</name>
<affiliation wicri:level="1"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5</wicri:regionArea>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
<wicri:noRegion>34093, Montpellier cedex 5</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">ChemMedChem</title>
<idno type="eISSN">1860-7187</idno>
<imprint><date when="2017" type="published">2017</date>
</imprint>
</series>
</biblStruct>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aeromonas hydrophila (enzymology)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Molecular Structure</term>
<term>Stenotrophomonas maltophilia (enzymology)</term>
<term>Structure-Activity Relationship</term>
<term>Thiones (chemical synthesis)</term>
<term>Thiones (chemistry)</term>
<term>Thiones (pharmacology)</term>
<term>Triazoles (chemical synthesis)</term>
<term>Triazoles (chemistry)</term>
<term>Triazoles (pharmacology)</term>
<term>beta-Lactamase Inhibitors (chemical synthesis)</term>
<term>beta-Lactamase Inhibitors (chemistry)</term>
<term>beta-Lactamase Inhibitors (pharmacology)</term>
<term>beta-Lactamases (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Aeromonas hydrophila (enzymologie)</term>
<term>Inhibiteurs des bêta-lactamases ()</term>
<term>Inhibiteurs des bêta-lactamases (pharmacologie)</term>
<term>Inhibiteurs des bêta-lactamases (synthèse chimique)</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Stenotrophomonas maltophilia (enzymologie)</term>
<term>Structure moléculaire</term>
<term>Thiones ()</term>
<term>Thiones (pharmacologie)</term>
<term>Thiones (synthèse chimique)</term>
<term>Triazoles ()</term>
<term>Triazoles (pharmacologie)</term>
<term>Triazoles (synthèse chimique)</term>
<term>bêta-Lactamases (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Thiones</term>
<term>Triazoles</term>
<term>beta-Lactamase Inhibitors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Thiones</term>
<term>Triazoles</term>
<term>beta-Lactamase Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Aeromonas hydrophila</term>
<term>Stenotrophomonas maltophilia</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Aeromonas hydrophila</term>
<term>Stenotrophomonas maltophilia</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>beta-Lactamases</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>bêta-Lactamases</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs des bêta-lactamases</term>
<term>Thiones</term>
<term>Triazoles</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Thiones</term>
<term>Triazoles</term>
<term>beta-Lactamase Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Inhibiteurs des bêta-lactamases</term>
<term>Thiones</term>
<term>Triazoles</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term>
<term>Molecular Structure</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Inhibiteurs des bêta-lactamases</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Structure moléculaire</term>
<term>Thiones</term>
<term>Triazoles</term>
</keywords>
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<front><div type="abstract" xml:lang="en">Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.</div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>Belgique</li>
<li>France</li>
<li>Italie</li>
<li>Turquie</li>
</country>
<region><li>Auvergne-Rhône-Alpes</li>
<li>Hambourg</li>
<li>Languedoc-Roussillon</li>
<li>Occitanie (région administrative)</li>
<li>Province de Liège</li>
<li>Rhône-Alpes</li>
<li>Région wallonne</li>
<li>Île-de-France</li>
</region>
<settlement><li>Grenoble</li>
<li>Hambourg</li>
<li>Liège</li>
<li>Montpellier</li>
<li>Paris</li>
</settlement>
<orgName><li>Université Joseph Fourier</li>
<li>Université Pierre-et-Marie-Curie</li>
<li>Université de Liège</li>
</orgName>
</list>
<tree><country name="France"><noRegion><name sortKey="Sevaille, Laurent" sort="Sevaille, Laurent" uniqKey="Sevaille L" first="Laurent" last="Sevaille">Laurent Sevaille</name>
</noRegion>
<name sortKey="Benard, Lionel" sort="Benard, Lionel" uniqKey="Benard L" first="Lionel" last="Bénard">Lionel Bénard</name>
<name sortKey="Condon, Ciaran" sort="Condon, Ciaran" uniqKey="Condon C" first="Ciaran" last="Condon">Ciaran Condon</name>
<name sortKey="Dideberg, Otto" sort="Dideberg, Otto" uniqKey="Dideberg O" first="Otto" last="Dideberg">Otto Dideberg</name>
<name sortKey="Gavara, Laurent" sort="Gavara, Laurent" uniqKey="Gavara L" first="Laurent" last="Gavara">Laurent Gavara</name>
<name sortKey="Guyon, Carole" sort="Guyon, Carole" uniqKey="Guyon C" first="Carole" last="Guyon">Carole Guyon</name>
<name sortKey="Hernandez, Jean Francois" sort="Hernandez, Jean Francois" uniqKey="Hernandez J" first="Jean-François" last="Hernandez">Jean-François Hernandez</name>
<name sortKey="Lonjon, Pauline" sort="Lonjon, Pauline" uniqKey="Lonjon P" first="Pauline" last="Lonjon">Pauline Lonjon</name>
<name sortKey="Maillard, Ludovic" sort="Maillard, Ludovic" uniqKey="Maillard L" first="Ludovic" last="Maillard">Ludovic Maillard</name>
<name sortKey="Martinez, Jean" sort="Martinez, Jean" uniqKey="Martinez J" first="Jean" last="Martinez">Jean Martinez</name>
<name sortKey="Nauton, Lionel" sort="Nauton, Lionel" uniqKey="Nauton L" first="Lionel" last="Nauton">Lionel Nauton</name>
</country>
<country name="Belgique"><region name="Région wallonne"><name sortKey="Bebrone, Carine" sort="Bebrone, Carine" uniqKey="Bebrone C" first="Carine" last="Bebrone">Carine Bebrone</name>
</region>
<name sortKey="Frere, Jean Marie" sort="Frere, Jean Marie" uniqKey="Frere J" first="Jean-Marie" last="Frère">Jean-Marie Frère</name>
<name sortKey="Galleni, Moreno" sort="Galleni, Moreno" uniqKey="Galleni M" first="Moreno" last="Galleni">Moreno Galleni</name>
<name sortKey="Mercuri, Paola" sort="Mercuri, Paola" uniqKey="Mercuri P" first="Paola" last="Mercuri">Paola Mercuri</name>
</country>
<country name="Italie"><noRegion><name sortKey="De Luca, Filomena" sort="De Luca, Filomena" uniqKey="De Luca F" first="Filomena" last="De Luca">Filomena De Luca</name>
</noRegion>
<name sortKey="Borgianni, Luisa" sort="Borgianni, Luisa" uniqKey="Borgianni L" first="Luisa" last="Borgianni">Luisa Borgianni</name>
<name sortKey="Docquier, Jean Denis" sort="Docquier, Jean Denis" uniqKey="Docquier J" first="Jean-Denis" last="Docquier">Jean-Denis Docquier</name>
<name sortKey="Tanfoni, Silvia" sort="Tanfoni, Silvia" uniqKey="Tanfoni S" first="Silvia" last="Tanfoni">Silvia Tanfoni</name>
</country>
<country name="Allemagne"><region name="Hambourg"><name sortKey="Achard, Maud" sort="Achard, Maud" uniqKey="Achard M" first="Maud" last="Achard">Maud Achard</name>
</region>
<name sortKey="Becker, Katja" sort="Becker, Katja" uniqKey="Becker K" first="Katja" last="Becker">Katja Becker</name>
<name sortKey="Dzieciolowski, Julia" sort="Dzieciolowski, Julia" uniqKey="Dzieciolowski J" first="Julia" last="Dzieciolowski">Julia Dzieciolowski</name>
</country>
<country name="Turquie"><noRegion><name sortKey="Turan Zitouni, Gulhan" sort="Turan Zitouni, Gulhan" uniqKey="Turan Zitouni G" first="Gülhan" last="Turan-Zitouni">Gülhan Turan-Zitouni</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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   |wiki=    Wicri/Asie
   |area=    AustralieFrV1
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   |type=    RBID
   |clé=     pubmed:28505394
   |texte=   1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.
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Serveur d'exploration sur les relations entre la France et l'Australie

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.

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English descriptors

Abstract

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	Serveur d'exploration sur les relations entre la France et l'Australie
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