title: 3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3.
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.
authors.affiliation: Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Fugel
authors.forename: Anselm Erich
authors.initials: AE
authors.lastname: Oberholzer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gschloessl
authors.forename: Ron
authors.initials: R
authors.lastname: Dzikowski
authors.forename: Narkiss
authors.initials: N
authors.lastname: Pressburger
authors.forename: Lutz
authors.initials: L
authors.lastname: Preu
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Blandine
authors.initials: B
authors.lastname: Baratte
authors.forename: Morgane
authors.initials: M
authors.lastname: Ratin
authors.forename: Ilya
authors.initials: I
authors.lastname: Okun
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kruggel
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemcke
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D009570:Nitriles; D011725:Pyridines; D013876:Thiophenes; D000255:Adenosine Triphosphate; D038362:Glycogen Synthase Kinase 3