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3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3 (PfGSK-3)

3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3 (PfGSK-3)

Authors :
Fugel, Wiebke
Oberholzer, Anselm Erich
Gschloessl, Bernhard
Dzikowski, Ron
Pressburger, Narkiss
Preu, Lutz
Pearl, Laurence H.
Baratte, Blandine
Ratin, Morgane
Okun, Illya
Doerig, Christian
Kruggel, Sebastian
Lemcke, Thomas
Meijer, Laurent
Kunick, Conrad
Technical University Braunschweig
Structural Biology Community Laenggasse
Partenaires INRAE
Centre de Biologie pour la Gestion des Populations (UMR CBGP)
Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)
Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Hadassah Medical School
Institute for Medical Research Israel-Canada
The Hebrew University Hadassah Medical School
The Hebrew University of Jerusalem (HUJ)
University of Sussex
Phophorylation de protéines et Pathologies Humaines (P3H)
Station biologique de Roscoff [Roscoff] (SBR)
Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Research and Development
Monash University
University of Hamburg
ManRos Therapeutics
University of Braunschweig
Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig]
Source :
Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩, Journal of Medicinal Chemistry, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩
Publication Year :
2013
Publisher :
HAL CCSD, 2013.

Abstract

International audience; Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (PfGSK-3) was suggested as a potential biological target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)2-benzoylthieno[2,3-b]pyridine-5-carbonitriles were discovered as a new class of PfGSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of PfGSK-3. Taking into account the Xray structure of a related molecule in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATPbinding pockets are responsible for the observed PfGSK-3 vs HsGSK-3 selectivity. Representatives of the title compound class exhibited micromolar IC50 values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.

Details

Language :
English
ISSN :
00222623 and 15204804
Database :
OpenAIRE
Journal :
Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩, Journal of Medicinal Chemistry, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩
Accession number :
edsair.dedup.wf.001..2d7f2f137e9435d7e41d7942f20d0c20
Full Text :
https://doi.org/10.1021/jm301575n⟩