Malaria is a major public health problem that affects millions of lives globally. The increased
burden of malaria requires new interventions that will address the eradication of the disease.
Current interventions include vector control by using insecticide-treated bed nets and indoor
residual spraying, and antimalarial drugs to control the parasite. Parasite resistance has
been reported for the currently used effective antimalarial drugs. To pre-empt the impact of
parasite resistance a continued development of new antimalarial drugs that have novel
mechanisms of action should be pursued. Antimalarial drug discovery requires that potential
antimalarial drugs should have different drug targets to those already targeted, to lower the
chances of resistance. Potential antimalarial drugs should preferably provide a single radical
cure to prevent reproduction at all life cycle stages.
This study tested the effects of in silico designed compounds targeting plasmodial Ca2+-
dependent protein kinases (CDPK) 1 & 4, FIKK kinases and bromodomain proteins on the
Plasmodium parasite. These enzymes are involved in gene regulation and are important
factors during gene transcription. In P. falciparum the gatekeeper kinases contain small
hydrophobic pockets near the ATP-binding site. These hydrophobic pockets allow for
selective inhibition of these proteins at the ATP-binding site. The compounds were tested in
vitro to determine their antiplasmodial activity. These compounds are shown to be potential
inhibitors of the intra-erythrocytic P. falciparum parasites as three of the compounds showed
selective cytotoxic activity at less than 1 μM against the chloroquine sensitive laboratory
strains (3D7 and NF54). Even though the proteins targeted by these compounds have been
previously indicated to play a role at specific stages during the parasite’s life cycle, the
compounds tested here were not able to target the sexual gametocyte stages of the
Plasmodium parasite. Further optimisation of these compounds should be performed to
improve activity against both the asexual and sexual stages of the parasites.