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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

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 relat...

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Published in:Journal of medicinal chemistry 2022-10, Vol.65 (19), p.13172-13197
Main Authors: Galal, Kareem A., Truong, Anna, Kwarcinski, Frank, de Silva, Chandi, Avalani, Krisha, Havener, Tammy M., Chirgwin, Michael E., Merten, Eric, Ong, Han Wee, Willis, Caleb, Abdelwaly, Ahmad, Helal, Mohamed A., Derbyshire, Emily R., Zutshi, Reena, Drewry, David H.
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container_end_page 13197
container_issue 19
container_start_page 13172
container_title Journal of medicinal chemistry
container_volume 65
creator Galal, Kareem A.
Truong, Anna
Kwarcinski, Frank
de Silva, Chandi
Avalani, Krisha
Havener, Tammy M.
Chirgwin, Michael E.
Merten, Eric
Ong, Han Wee
Willis, Caleb
Abdelwaly, Ahmad
Helal, Mohamed A.
Derbyshire, Emily R.
Zutshi, Reena
Drewry, David H.
description 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.
doi_str_mv 10.1021/acs.jmedchem.2c00996
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title Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro
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