The development of chemical inhibitors against the metalloprotease falcylisin

SMSU Event Center BC

Plasmodium falciparum is the cause of more than 500,000 fatal malaria cases a year with most being in African children. Falcylisin is a metalloprotease that is important to the parasite cell for growth within human cells. Our goal is to synthesize inhibitors against falcylisin so that loss of function studies can be done to better understand the biological functions of the protease . We are using piperazine-based hydroxamic acids with multiple substituents at the N-1 and N-4 position to find what groups would fit and interact the best with falcylisin active site. Each compound contains a hydroxamic acid group to coordinate with the zinc at the active site of the protease. We tested multiple different substituents ranging from small and large amides, amides with electron withdrawing groups, sulfonamides, and small aryl amines. Each inhibitor was tested for activity against falcylisin and cultured parasites. We have found that bulky aromatic groups have had the most success at the N-4 position. Further research is being done on the N-1 position because it has not seen a variety of different substituents. The N-4 position is also being further tested with different large aryl amides to optimize the compounds potency versus falcylisin.