New amidated 3,6-diphenylated imidazopyridazines with potent antiplasmodium activity are dual inhibitors of Plasmodium phosphatidylinositol-4-kinase and cGMP-dependent protein kinase

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Authors

Cheuka, Peter Mubanga
Centani, Luyanda
Arendse, Lauren B.
Fienberg, Stephen
Wambua, Lynn
Renga, Shoneeze S.
Dziwornu, Godwin Akpeko
Kumar, Malkeet
Lawrence, Nina
Taylor, Dale

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American Chemical Society

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 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 < 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 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.

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Keywords

Amides, Peptides and proteins, Parasites, Photovoltaics, Inhibition, Cyclic guanidine monophosphate (cGMP), Protein kinase (PKG), Adenosine triphosphate (ATP), Plasmodium phosphatidylinositol-4-kinase (PI4K)

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Citation

heuka, P.M., Centani, L., Arendse, L.B. et al. 2021, '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, vol. 7, no. 1, pp. 34-46.