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

Abstract

Essential plasmodial kinases <i>Pf</i>GSK3 and <i>Pf</i>PK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of <b>IKK16</b> as a dual <i>Pf</i>GSK3/<i>Pf</i>PK6 inhibitor active against blood stage <i>Pf</i>3D7 parasites. To establish structure-activity relationships for <i>Pf</i>PK6 and <i>Pf</i>GSK3, 52 analogues were synthesized and assessed for the inhibition of <i>Pf</i>GSK3 and <i>Pf</i>PK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual <i>Pf</i>GSK3/<i>Pf</i>PK6 inhibitors <b>23d</b> (<i>Pf</i>GSK3/<i>Pf</i>PK6 IC₅₀ = 172/11 nM) and <b>23e</b> (<i>Pf</i>GSK3/<i>Pf</i>PK6 IC₅₀ = 97/8 nM) with antiplasmodial activity (<b>23d</b> <i>Pf</i>3D7 EC₅₀ = 552 ± 37 nM and <b>23e</b> <i>Pf</i>3D7 EC₅₀ = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual <i>Pf</i>PK6/<i>Pf</i>GSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.