Novel Scaffold Unlocks Potent Cross-Peptidase and Cross-Species Inhibitors as Promising Antimalarial Agents

Malaria remains a global health burden and the emergence of parasite-resistance to frontline drugs highlights an urgent need for new therapeutics with novel mechanisms of action. Inhibiting aminopeptidases, in particular the <i>Plasmodium falciparum</i> M1 and M17 aminopeptidases (<i>Pf</i>A-M1 and <i>Pf</i>A-M17 respectively) has been shown to cause parasite death. In this study, both ligand-based and structure-based design strategies were utilized to identify novel scaffolds that act as dual inhibitors of these enzymes. Structural studies supported the improved activity showing strong hydrophobic and additional hydrogen interactions between the new cores and the S1 pocket of the enzymes. These inhibitors were highly effective against <i>Plasmodium vivax</i> and <i>Plasmodium berghei</i>, showing cross-peptidase and cross-species activity while also retaining activity against multidrug resistant <i>P. falciparum</i> strains. Progression to <i>in vivo</i> efficacy studies showed reduction in parasitaemia in mice infected with <i>P. berghei</i> demonstrating encouraging prospects to develop suitable drug-like candidates for the treatment of malaria.