2 research outputs found
High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum
In this study, we identified three novel compound classes
with
potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this
pathogen to known drugs is increasing, and compounds with different
modes of action are urgently needed. One promising drug target is
the enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS)
of the methylerythritol 4-phosphate (MEP) pathway for which we have
previously identified three active compound classes against Mycobacterium tuberculosis. The close structural
similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes
display good cell-based activity. Through structure–activity
relationship studies, we increased their antimalarial potency and
two classes also show good metabolic stability and low toxicity against
human liver cells. The most active compound 1 inhibits
the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different
methods for target validation of compound 1 suggest no
engagement of DXPS. All inhibitor classes are active against chloroquine-resistant
strains, confirming a new mode of action that has to be further investigated
High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum
In this study, we identified three novel compound classes
with
potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this
pathogen to known drugs is increasing, and compounds with different
modes of action are urgently needed. One promising drug target is
the enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS)
of the methylerythritol 4-phosphate (MEP) pathway for which we have
previously identified three active compound classes against Mycobacterium tuberculosis. The close structural
similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes
display good cell-based activity. Through structure–activity
relationship studies, we increased their antimalarial potency and
two classes also show good metabolic stability and low toxicity against
human liver cells. The most active compound 1 inhibits
the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different
methods for target validation of compound 1 suggest no
engagement of DXPS. All inhibitor classes are active against chloroquine-resistant
strains, confirming a new mode of action that has to be further investigated