136633-80-2Relevant articles and documents
3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3- b ]pyridine-5- carbonitriles are selective inhibitors of plasmodium falciparum glycogen synthase kinase-3
Fugel, Wiebke,Oberholzer, Anselm Erich,Gschloessl, Bernhard,Dzikowski, Ron,Pressburger, Narkiss,Preu, Lutz,Pearl, Laurence H.,Baratte, Blandine,Ratin, Morgane,Okun, Ilya,Doerig, Christian,Kruggel, Sebastian,Lemcke, Thomas,Meijer, Laurent,Kunick, Conrad
supporting information, p. 264 - 275 (2013/03/13)
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.
