3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3

Wiebke Fugel, Anselm E Oberholzer, Bernhard Gschloessl, Ron Dzikowski, Narkiss Pressburger, Lutz Preu, Laurence H Pearl, Blandine Baratte, Morgane Ratin, Ilya Okun, Christian Daniel Doerig, Sebastian Kruggel, Thomas Lemckert, Laurent Meijer, Conrad Kunick

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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 IC(5)(0) values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.
Original languageEnglish
Pages (from-to)264 - 275
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number1
Publication statusPublished - 2013

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