Human malaria is a parasitic disease caused by 6 different Plasmodium species, leading to approximately 600,000 annual deaths. All clinical symptoms of the disease result from the intraerythrocytic development of the parasite. During this part of the life cycle, the parasite expresses an array of proteases to carry out many essential processes, such as host cell protein degradation, host cell invasion, and parasite protein export. Falcilysin (FLN) is an essential metalloprotease expressed by the parasite during intraerythrocytic infection, and it is known to function in host hemoglobin degradation and in processing of apicoplast-targeted parasite proteins. Recent studies have identified FLN as a target of the clinical antimalarial drug chloroquine, and it appears likely that the protease carries out additional roles in the cell.<br/>We are developing chemical tools to enable further investigation of FLN biology and its potential as a chemotherapeutic target. Here we report our work to synthesize and evaluate a series of piperazine-based hydroxamic acids as inhibitors of FLN. These efforts focus on elucidating SAR for this inhibitor scaffold against the metalloprotease, as well as on incorporating photocrosslinking and click chemistry moieties into the scaffold. These studies will provide the rationale for the development of increasingly potent FLN inhibitors while identifying possible off-targets in the cell.<br/>This work builds upon our previous research by further optimizing the N1 and N4 positions on the piperazine core. We synthesized and tested a series of 20+ compounds with diverse substituents which were installed using a range of synthetic methodologies. In a subset of compounds we incorporated diazirine and alkyne moieties to enable identification of cellular targets using a combination of photocrosslinking and click chemistry. All compounds were tested against cultured parasites and purified FLN, and we identified additional structural requirements for potent inhibition of FLN. Multiple inhibitors were discovered with similar or improved potency relative to our previous lead compounds.

Development of photocrosslinking click chemistry probes to investigate the function of falcilysin, an essential malarial metalloprotease

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