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3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3 (PfGSK-3)
3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3 (PfGSK-3)
- Source :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩, Journal of Medicinal Chemistry, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩
- Publication Year :
- 2013
- Publisher :
- HAL CCSD, 2013.
-
Abstract
- International audience; 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 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 ATPbinding 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.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩, Journal of Medicinal Chemistry, 2013, 56 (1), pp.264-275. ⟨10.1021/jm301575n⟩
- Accession number :
- edsair.dedup.wf.001..2d7f2f137e9435d7e41d7942f20d0c20
- Full Text :
- https://doi.org/10.1021/jm301575n⟩