3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3
详细信息 查看全文
- 作者：Wiebke Fugel ; Anselm Erich Oberholzer ; Bernhard Gschloessl ; Ron Dzikowski ; Narkiss Pressburger ; Lutz Preu ; Laurence H. Pearl ; Blandine Baratte ; Morgane Ratin ; Ilya Okun ; Christian Doerig ; Sebastian Kruggel ; Thomas Lemcke ; Laurent Meijer ; Conrad Kunick
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：January 10, 2013
- 年：2013
- 卷：56
- 期：1
- 页码：264-275
- 全文大小：556K
- 年卷期：v.56,no.1(January 10, 2013)
- ISSN：1520-4804
文摘
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.