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The plasmodial kinases PfGSK3 and PfPK6 have been identified as essential for the asexual life stage of Plasmodium falciparum, and thus are considered viable novel drug targets to combat rising resistance to traditional antimalarial drugs. We recently identified disubstituted pyrimidine IKK16 as a compound which demonstrated strong activity against blood stage Pf3D7 parasites, while also exhibiting potent activity against PfGSK3 and PfPK6. Here we describe the synthesis of a series of IKK16 analogues and efforts to establish structure activity relationships to develop compounds with enhanced inhibition of PfPK6 and PfGSK3. We made extensive modifications focused on the 2, 4, and 5 positions of the pyrimidine core. The new synthesized compounds were assessed for enzymatic activity on PfGSK3 and PfPK6 using a split luciferase binding assay, and many of them displayed low nanomolar potency against both kinases. The most potent inhibitors were further assessed for activity against blood stage P. falciparum 3D7 parasites as well as liver stage P. berghei parasites. This culminated in the discovery of compounds 23d and 23e which displayed the most promising biological profiles among this set of analogues. Both compounds showed the greatest inhibitory activity against PfGSK3 and PfPK6 (23d PfGSK3 IC50 = 172 nM, PfPK6 IC50 = 11 nM, 23e PfGSK3 IC50 = 97 nM, PfPK6 IC50 = 8 nM) and demonstrated considerable activity against blood stage parasitemia (23d Pf3D7 EC50 = 552 nM, 23e Pf3D7 EC50 = 1400 nM). Also, the ligand efficiency of these compounds was greater than IKK16. Both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Taken together, our results suggest that dual PfPK6/PfGSK3 inhibitors with antiplasmodial activity can be identified. Our strategy of targeting two plasmodial kinases simultaneously and the structure activity results described herein sets the stage for further optimization efforts with the goal of identifying novel antiplasmodial agents.