3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitri les Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3

作者：Fugel Wiebke; Oberholzer Anselm Erich; Gschloessl Bernhard; Dzikowski Ron; Pres**urger Narkiss; Preu Lutz; Pearl Laurence H; Baratte Blandine; Ratin Morgane; Okun Ilya; Doerig Christian; Kruggel Sebastian; Lemcke Thomas; Meijer Laurent^*; Kunick Conrad

来源：Journal of Medicinal Chemistry, 2013, 56(1): 264-275.

DOI：10.1021/jm301575n

Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (Pf GSK-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 Pf GSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of Pf GSK-3. Taking into account the Xray 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 Pf GSK-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 Pf GSK-3 could be developed as potential antimalarial drugs.

• 出版日期2013-1-10
• 单位河北医科大学