3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3
| Autor: | Laurent Meijer, Narkiss Pressburger, Wiebke Fugel, Ilya Okun, Anselm Erich Oberholzer, Lutz Preu, Ron Dzikowski, Morgane Ratin, Blandine Baratte, Sebastian Kruggel, B Gschloessl, Christian Doerig, Conrad Kunick, Laurence H. Pearl, Thomas Lemcke |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Stereochemistry
Pyridines Plasmodium falciparum Plasma protein binding Thiophenes Crystallography X-Ray 01 natural sciences 03 medical and health sciences Antimalarials Glycogen Synthase Kinase 3 Structure-Activity Relationship Adenosine Triphosphate Parasitic Sensitivity Tests GSK-3 Drug Discovery Nitriles Structure–activity relationship Humans Glycogen synthase 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology 010405 organic chemistry biology.organism_classification 3. Good health 0104 chemical sciences High-Throughput Screening Assays Molecular Docking Simulation Enzyme Biochemistry chemistry Biological target biology.protein Molecular Medicine Selectivity Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry; Vol 56 |
| ISSN: | 0022-2623 |
| DOI: | 10.1021/jm301575n |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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