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Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro.

Publication ,  Journal Article
Galal, KA; Truong, A; Kwarcinski, F; de Silva, C; Avalani, K; Havener, TM; Chirgwin, ME; Merten, E; Ong, HW; Willis, C; Abdelwaly, A ...
Published in: Journal of medicinal chemistry
October 2022

Essential plasmodial kinases PfGSK3 and PfPK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual PfGSK3/PfPK6 inhibitor active against blood stage Pf3D7 parasites. To establish structure-activity relationships for PfPK6 and PfGSK3, 52 analogues were synthesized and assessed for the inhibition of PfGSK3 and PfPK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual PfGSK3/PfPK6 inhibitors 23d (PfGSK3/PfPK6 IC50 = 172/11 nM) and 23e (PfGSK3/PfPK6 IC50 = 97/8 nM) with antiplasmodial activity (23dPf3D7 EC50 = 552 ± 37 nM and 23ePf3D7 EC50 = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual PfPK6/PfGSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.

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Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

October 2022

Volume

65

Issue

19

Start / End Page

13172 / 13197

Related Subject Headings

  • Structure-Activity Relationship
  • Pyrimidines
  • Plasmodium falciparum
  • Plasmodium
  • Parasites
  • Medicinal & Biomolecular Chemistry
  • Humans
  • Glycogen Synthase Kinase 3
  • Antimalarials
  • Animals
 

Citation

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Galal, K. A., Truong, A., Kwarcinski, F., de Silva, C., Avalani, K., Havener, T. M., … Drewry, D. H. (2022). Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro. Journal of Medicinal Chemistry, 65(19), 13172–13197. https://doi.org/10.1021/acs.jmedchem.2c00996
Galal, Kareem A., Anna Truong, Frank Kwarcinski, Chandi de Silva, Krisha Avalani, Tammy M. Havener, Michael E. Chirgwin, et al. “Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro.Journal of Medicinal Chemistry 65, no. 19 (October 2022): 13172–97. https://doi.org/10.1021/acs.jmedchem.2c00996.
Galal KA, Truong A, Kwarcinski F, de Silva C, Avalani K, Havener TM, et al. Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro. Journal of medicinal chemistry. 2022 Oct;65(19):13172–97.
Galal, Kareem A., et al. “Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro.Journal of Medicinal Chemistry, vol. 65, no. 19, Oct. 2022, pp. 13172–97. Epmc, doi:10.1021/acs.jmedchem.2c00996.
Galal KA, Truong A, Kwarcinski F, de Silva C, Avalani K, Havener TM, Chirgwin ME, Merten E, Ong HW, Willis C, Abdelwaly A, Helal MA, Derbyshire ER, Zutshi R, Drewry DH. Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro. Journal of medicinal chemistry. 2022 Oct;65(19):13172–13197.
Journal cover image

Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

October 2022

Volume

65

Issue

19

Start / End Page

13172 / 13197

Related Subject Headings

  • Structure-Activity Relationship
  • Pyrimidines
  • Plasmodium falciparum
  • Plasmodium
  • Parasites
  • Medicinal & Biomolecular Chemistry
  • Humans
  • Glycogen Synthase Kinase 3
  • Antimalarials
  • Animals