New Amidated 3,6-Diphenylated Imidazopyridazines with Potent Antiplasmodium Activity Are Dual Inhibitors of Plasmodium Phosphatidylinositol-4-kinase and cGMP-Dependent Protein Kinase

Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive in vitro activity and in vivo efficacy in mouse models of malaria infection. Herein, we report the synthesis and antiplasmodium evaluation of a new series of amidated analogues and demonstrate that these compounds potently inhibit Plasmodium phosphatidylinositol-4-kinase (PI4K) type IIIβ while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) activity in vitro. Using in silico docking, we predict key binding interactions for these analogues within the adenosine triphosphate (ATP)-binding site of PI4K and PKG, paving the way for structure-based optimization of imidazopyridazines targeting both Plasmodium PI4K and PKG. While several derivatives showed low nanomolar antiplasmodium activity (IC50 28, resulted in strong dual PI4K and PKG inhibition. The compounds also demonstrated transmission-blocking potential, evident from their potent inhibition of early- and late-stage gametocytes. Finally, the current compounds generally showed improved aqueous solubility and reduced hERG (human ether-a-go-go-related gene) channel inhibition.