Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

Abstract

Graphical abstract

Extended-spectrum antiprotozoal bumped kinase inhibitors: A review

“…This selective difference in activity is sufficiently great to offer hope that further chemical elaboration, in particular of the R2 group, may allow distinguishing selectively between threonine-gatekeeper kinases of parasite and host. This extends the range of parasitic diseases potentially treatable with BKI drugs to include those caused by Plasmodium (Chapman, et al, 2013), Eimeria (Keyloun, et al, 2014), Theileria (Hines, et al, 2015), and Babesia (Pedroni, et al, 2016), all of which express threonine gatekeeper CDPKs. A validation of CDPK(s) as the sole molecular target(s) that cause inhibition of growth and proliferation of an apicomplexan parasite cells when exposed to BKIs will still need chemical genetic determination as demonstrated in T. gondii.…”

“…Two other BKI scaffolds (Fig. 2) that do not preserve this precise geometry of presenting substituents have also been explored to target apicomplexan CDPKs, imidazopyridazines to target Pf CDPK1 (Chapman, et al, 2013, Chapman, et al, 2014, Green, et al, 2016), and benzoylbenzimidazoles to target Tg CDPK1 and Cp CDPK1 (Zhang, et al, 2012). …”

Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues

“…Inhibition of the function of this enzyme is thought to represent a novel mechanism for malaria treatment 7 . We recently reported the discovery of a series of potent and selective imidazopyridazine inhibitors of Pf CDPK1 8 . These compounds, of type 1 (Fig.…”

Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans

“…One of the most potent of these called purfalcamine blocked late stage schizogony 93 , although the specific target of this inhibitor in the parasite remains uncertain. Using similar in vitro enzyme assays for small molecule screens, a number of other chemical series have emerged as potential inhibitors of PfCDPK1, including pyrazolopyrimidines, azabenzimididazoles, and imidazopyridazines 74, 75, 77 . The small Thr gatekeeper of PfCDPK1 was important in its susceptibility to these inhibitors in vitro ; however, the potency of enzyme inhibition in vitro was not correlated with inhibition of parasite growth in red blood cells 74 .…”