New Amidated 3,6-Diphenylated Imidazopyridazines With Potent Antiplasmodium Activity Are Dual Inhibitors Of Plasmodium Phosphatidylinositol-4-Kinase And Cgmp-Dependent Protein Kinase
ACS INFECTIOUS DISEASES(2021)
Abstract
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 III beta 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 < 100 nM), some compounds, including piperazine analogue 28, resulted in strong dual PI4K and PKG inhibition. The compounds also demonstrated transmission-blocking potential, evident from their potent inhibition of earlyand late-stage gametocytes. Finally, the current compounds generally showed improved aqueous solubility and reduced hERG (human ether-a-go-go-related gene) channel inhibition.
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Key words
antiplasmodium, antimalarial, imidazopyridazines, malaria, phosphatidylinositol-4-kinase (PI4K), cGMP-dependent protein kinase (PKG)
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