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

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.

journal_name

ACS Infect Dis

journal_title

ACS infectious diseases

authors

Cheuka PM,Centani L,Arendse LB,Fienberg S,Wambua L,Renga SS,Dziwornu GA,Kumar M,Lawrence N,Taylor D,Wittlin S,Coertzen D,Reader J,van der Watt M,Birkholtz LM,Chibale K

doi

10.1021/acsinfecdis.0c00481

subject

Has Abstract

pub_date

2021-01-08 00:00:00

pages

34-46

issue

1

issn

2373-8227

journal_volume

7

pub_type

杂志文章

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