The Apicomplexan parasite Plasmodium falciparum is the main causative agent for the most lethal form of human malaria. Current frontline anti-malarial treatments are being compromised by the increasing prevalence of multi-drug resistant strains of P. falciparum, and their rapid spread across the world. The need for new anti-malarial drugs with novel mechanisms of action has never been more urgent.

Blood stage malaria parasites grow extremely rapidly, and experience high levels of protein synthesis and turnover. They rely on active protein chaperone systems to maintain the integrity of their synthesized proteins, which makes them attractive targets for anti-malarial compounds. Recent studies towards the validation of plasmodial protein chaperones as anti-malarial drug targets have focused on Heat shock proteins (Hsp) -70 and -90, while the Hsp-100 chaperones have not been investigated. Recently, the small molecule N²,N⁴-dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a specific inhibitor of the human Hsp-100 chaperone, p97, and is currently being pursued as an anti-cancer drug.

To explore the possibility of DBeQ as an anti-malarial agent, we used a medicinal chemistry approach to create a diverse chemical compound library of 15 DBeQ analogues. Chemical modification to DBeQ resulted in a decrease in the IC₅₀ of the DBeQ analogues by two-fold against parasite growth compared to unmodified DBeQ (68 nM vs. 169 nM, respectively). The synthesized DBeQ analogues are also 10 times more active against P. falciparum parasites compared to cultured human breast cancer cells. Further modifications to the DBeQ scaffold will be pursued to improve this ratio in the human host’s favour. Future work will also be undertaken to determine which of the two P. falciparum p97 orthologues are the biological target of DBeQ.