2. Academic Validation
  3. Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial Pf GSK3/ Pf PK6 with Activity against Blood Stage Parasites In Vitro

Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial Pf GSK3/ Pf PK6 with Activity against Blood Stage Parasites In Vitro

  • J Med Chem. 2022 Oct 13;65(19):13172-13197. doi: 10.1021/acs.jmedchem.2c00996.
Kareem A Galal 1,  Anna Truong 2,  Frank Kwarcinski 3,  Chandi de Silva 3,  Krisha Avalani 3,  Tammy M Havener 1,  Michael E Chirgwin 2,  Eric Merten 1,  Han Wee Ong 1,  Caleb Willis 3,  Ahmad Abdelwaly 4,  Mohamed A Helal 4 5,  Emily R Derbyshire 2 6,  Reena Zutshi 3,  David H Drewry 1 7
Affiliations

Affiliations

  • 1 Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Department of Chemistry, Duke University, 124 Science Drive, Durham, North Carolina 27708, United States.
  • 3 Luceome Biotechnologies, L.L.C, 1665 E. 18th Street, Suite 106, Tucson, Arizona 85719, United States.
  • 4 Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza 12587, Egypt.
  • 5 Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
  • 6 Department of Molecular Genetics and Microbiology, Duke University Medical Center, 213 Research Drive, Durham, North Carolina 27710, United States.
  • 7 Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 36166733 DOI: 10.1021/acs.jmedchem.2c00996
Abstract

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 (23d Pf3D7 EC50 = 552 ± 37 nM and 23e Pf3D7 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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