Presentation Title

Development of Piperazine-derived Hydroxamic Acid Inhibitors to Investigate the Function of Falcilysin, an Essential Malarial Protease

Faculty Mentor

Jeremy Mallari

Start Date

17-11-2018 8:30 AM

End Date

17-11-2018 10:30 AM

Location

CREVELING 54

Session

POSTER 1

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

The malarial parasite Plasmodium falciparum kills approximately 500,000 people a year, with many of these fatalities occurring in African children. The parasite requires the metalloprotease falcilysin (FLN) for its development in the human host, but the biological role of this metalloprotease is poorly understood. Our group is working to develop selective FLN inhibitors in order to generate chemical tools to probe the biology of this protease in live parasites. We recently reported a series of FLN inhibitors based on a piperazine-derived hydroxamic acid scaffold. In these studies, we found that incorporation of a bulky biphenyl moiety at N4 position of the piperazine ring resulted in potent activity against FLN. In the current study, we further optimized the N4 substituent by testing a homologation series to probe the depth of the corresponding binding pocket in FLN. In addition, we tested the effect of utilizing different functional groups (amine, amide, and sulfonamide) in the N4 linker. We determined that effective FLN inhibition requires a bulky hydrophobic group tethered at the N4 position by at least 4 carbons. We tested 1, 2, 3, and 4 carbon linkages and found that linkers of 1-3 carbons were significantly less active than using either a phenyl or butaryl linker. We also found that incorporating different functional groups at the linkage strongly affects the FLN inhibition, and utilizing a sulfonamide moiety increased inhibitor potency more than twenty-fold when compared amide and amine linkages.

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Nov 17th, 8:30 AM Nov 17th, 10:30 AM

Development of Piperazine-derived Hydroxamic Acid Inhibitors to Investigate the Function of Falcilysin, an Essential Malarial Protease

CREVELING 54

The malarial parasite Plasmodium falciparum kills approximately 500,000 people a year, with many of these fatalities occurring in African children. The parasite requires the metalloprotease falcilysin (FLN) for its development in the human host, but the biological role of this metalloprotease is poorly understood. Our group is working to develop selective FLN inhibitors in order to generate chemical tools to probe the biology of this protease in live parasites. We recently reported a series of FLN inhibitors based on a piperazine-derived hydroxamic acid scaffold. In these studies, we found that incorporation of a bulky biphenyl moiety at N4 position of the piperazine ring resulted in potent activity against FLN. In the current study, we further optimized the N4 substituent by testing a homologation series to probe the depth of the corresponding binding pocket in FLN. In addition, we tested the effect of utilizing different functional groups (amine, amide, and sulfonamide) in the N4 linker. We determined that effective FLN inhibition requires a bulky hydrophobic group tethered at the N4 position by at least 4 carbons. We tested 1, 2, 3, and 4 carbon linkages and found that linkers of 1-3 carbons were significantly less active than using either a phenyl or butaryl linker. We also found that incorporating different functional groups at the linkage strongly affects the FLN inhibition, and utilizing a sulfonamide moiety increased inhibitor potency more than twenty-fold when compared amide and amine linkages.