The malaria parasite, Plasmodium falciparum, kills an estimated 445,000 people annually, with the most deaths occurring in African children. Previous studies show that falcilysin (FLN) is a metalloprotease essential to the parasite’s development in the human host, though its biological role is poorly understood. The parasite is notoriously resistant to genetic modification. To study the cellular roles of FLN, we are developing piperazine-derived hydroxamic acids to block FLN activity in cultured parasites in order to conduct loss-of-function studies. Previous data demonstrates that the active site of the metalloprotease is highly receptive to bulky non-polar substituents at the N4 position of the inhibitor scaffold. In this study, we synthesized several inhibitors with different combination of linkers and aryl substituents at the N4-position. Compound potency was determined against recombinant FLN and cultured P. falciparum. Tethering a phenyl ring through a lengthy alkyl chain with an N4-sulfonamide linkage resulted in significantly increased potency against the protease target. These data will guide the further development of chemical tools to probe the function of this protease and to help evaluate FLN as a potential therapeutic target.

Developing chemical probes against falcilysin, an essential malarial metalloprotease

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.