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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Abstract

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
Volume56
Issue number1
DOIs
Publication statusPublished - 2013

Cite this

Fugel, Wiebke ; Oberholzer, Anselm E ; Gschloessl, Bernhard ; Dzikowski, Ron ; Pressburger, Narkiss ; Preu, Lutz ; Pearl, Laurence H ; Baratte, Blandine ; Ratin, Morgane ; Okun, Ilya ; Doerig, Christian Daniel ; Kruggel, Sebastian ; Lemckert, Thomas ; Meijer, Laurent ; Kunick, Conrad. / 3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 1. pp. 264 - 275.
@article{c54cead7799b4257984edf76f9c02978,
title = "3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3",
abstract = "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.",
author = "Wiebke Fugel and Oberholzer, {Anselm E} and Bernhard Gschloessl and Ron Dzikowski and Narkiss Pressburger and Lutz Preu and Pearl, {Laurence H} and Blandine Baratte and Morgane Ratin and Ilya Okun and Doerig, {Christian Daniel} and Sebastian Kruggel and Thomas Lemckert and Laurent Meijer and Conrad Kunick",
year = "2013",
doi = "10.1021/jm301575n",
language = "English",
volume = "56",
pages = "264 -- 275",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "1",

}

Fugel, W, Oberholzer, AE, Gschloessl, B, Dzikowski, R, Pressburger, N, Preu, L, Pearl, LH, Baratte, B, Ratin, M, Okun, I, Doerig, CD, Kruggel, S, Lemckert, T, Meijer, L & Kunick, C 2013, '3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3', Journal of Medicinal Chemistry, vol. 56, no. 1, pp. 264 - 275. https://doi.org/10.1021/jm301575n

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

In: Journal of Medicinal Chemistry, Vol. 56, No. 1, 2013, p. 264 - 275.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3

AU - Fugel, Wiebke

AU - Oberholzer, Anselm E

AU - Gschloessl, Bernhard

AU - Dzikowski, Ron

AU - Pressburger, Narkiss

AU - Preu, Lutz

AU - Pearl, Laurence H

AU - Baratte, Blandine

AU - Ratin, Morgane

AU - Okun, Ilya

AU - Doerig, Christian Daniel

AU - Kruggel, Sebastian

AU - Lemckert, Thomas

AU - Meijer, Laurent

AU - Kunick, Conrad

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://pubs.acs.org/doi/pdf/10.1021/jm301575n

U2 - 10.1021/jm301575n

DO - 10.1021/jm301575n

M3 - Article

VL - 56

SP - 264

EP - 275

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -