Quinoid compounds cause inhibition of falcipain 2, and arrest Plasmodium falciparum growth in vitro

Nine quinone derivatives, three 2-hydroxy-1,4-naphthoquinone; three 4,5 and three 4,9-naphthoquinone scaffolds, were synthesized and evaluated against 3D7 and Dd2 Plasmodium falciparum strains. Quinoid compounds showed half-maximal inhibitory concentration (IC50) values in the micromolar range, and moderate toxicity against a human fibroblast cell line. Additionally, the compounds produced morphological changes in the digestive vacuole of treated parasites, similar to those caused by protease inhibitors that block hemoglobin degradation pathway, which is essential for parasite development. 2-hydroxy-3-(1-propenyl)-1,4- naphthoquinone (1) showed an IC50 value of 0.068 ± 0.035 μM against FP2, a chemotherapeutic target, and thus representing a lead compound for further structure/activity optimization. Taken together, our results suggest that blocking of hemoglobin degradation pathway by inhibiting the cysteine peptidases present in the digestive vacuole, could represent one of the mechanisms used by these compounds to antagonize the growth of malaria parasites.