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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

DOI: 10.1021/jm301575n DOI Help
PMID: 23214499 PMID Help

Authors: Wiebke Fugel (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig) , Anselm Erich Oberholzer (Structural Biology Community Laenggasse (sbcl)) , Bernhard Gschloessl (Centre de Biologie pour la Gestion des Populations (CBGP), UMR1062, Institut National de la Recherche Agronomique (INRA)) , Ron Dzikowski (Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School) , Narkiss Pressburger (Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School) , Lutz Preu (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig) , Laurence H. Pearl (University of Sussex) , Blandine Baratte (Protein Phosphorylation & Human Disease Group, CNRS USR 3151) , Morgane Ratin (Protein Phosphorylation & Human Disease Group, CNRS USR 3151) , Ilya Okun (ChemDiv, Inc.) , Christian Doerig (Monash University) , Sebastian Kruggel (Universität Hamburg) , Thomas Lemcke (Universität Hamburg) , Laurent Meijer (Protein Phosphorylation & Human Disease Group, CNRS USR 3151; ManRos Therapeutics) , Conrad Kunick (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56 (1) , PAGES 264 - 275

State: Published (Approved)
Published: January 2013
Diamond Proposal Number(s): 8015

Abstract: 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 X-ray 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 ATP-binding 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.

Journal Keywords: Antimalarials; Crystallography; X-Ray; Glycogen; High-Throughput; Humans; Molecular; Nitriles; Parasitic; Plasmodium; Protein; Pyridines; Structure-Activity; Thiophenes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography