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

Cheuka, Peter MubangaCentani, LuyandaArendse, Lauren B.Fienberg, StephenWambua, LynnRenga, Shoneeze S.Dziwornu, Godwin AkpekoKumar, MalkeetLawrence, NinaTaylor, DaleWittlin, SergioCoertzen, DinaReader, JanetteVan der Watt, Mariette ElizabethBirkholtz, Lyn-MarieChibale, Kelly2021-12-152021-12-152021-01heuka, 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. 34-46.2373-8227 (print)2373-8227 (online)aidcbc10.1021/acsinfecdis.0c00481http://hdl.handle.net/2263/83065Recent 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.en© 2020 American Chemical SocietyAmidesPeptides and proteinsParasitesPhotovoltaicsInhibitionCyclic guanidine monophosphate (cGMP)Protein kinase (PKG)Adenosine triphosphate (ATP)Plasmodium phosphatidylinositol-4-kinase (PI4K)New amidated 3,6-diphenylated imidazopyridazines with potent antiplasmodium activity are dual inhibitors of Plasmodium phosphatidylinositol-4-kinase and cGMP-dependent protein kinasePostprint Article