Development of piperazine-based hydroxamic acid inhibitors against falcilysin, an essential malarial protease

Jeffrey P Chance; Hannah Fejzic; Obiel Hernandez; Eva S Istvan; Armann Andaya; Nikolay Maslov; Ruby Aispuro; Teodulo Crisanto; Huyen Nguyen; Brian Vidal; Whitney Serrano; Bradley Kuwahara; Corey Pugne Andanado; Daniel E Goldberg; Jeremy P Mallari

doi:10.1016/j.bmcl.2018.04.010

Development of piperazine-based hydroxamic acid inhibitors against falcilysin, an essential malarial protease

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1846-1848. doi: 10.1016/j.bmcl.2018.04.010. Epub 2018 Apr 19.

Authors

Affiliations

¹ Department of Chemistry and Biochemistry, California State University, San Bernardino, USA.
² Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, USA.
³ Campus Mass Spectrometry Facilities, University of California, Davis, USA.
⁴ Department of Chemistry and Biochemistry, California State University, San Bernardino, USA. Electronic address: [email protected].

PMID: 29691139
DOI: 10.1016/j.bmcl.2018.04.010

Abstract

The human parasite Plasmodium falciparum kills an estimated 445,000 people a year, with the most fatalities occurring in African children. Previous studies identified falcilysin (FLN) as a malarial metalloprotease essential for parasite development in the human host. Despite its essentiality, the biological roles of this protease are not well understood. Here we describe the optimization of a piperazine-based hydroxamic acid scaffold to develop the first reported inhibitors of FLN. Inhibitors were tested against cultured parasites, and parasiticidal activity correlated with potency against FLN. This suggests these compounds kill P. falciparum by blocking FLN, and that FLN is a druggable target. These compounds represent an important step towards validating FLN as a therapeutic target and towards the development of chemical tools to investigate the function of this protease.

Keywords: Falcilysin; Hydroxamic acid; Malaria; Metalloprotease; Protease inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry*
Antimalarials / pharmacology
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry*
Hydroxamic Acids / pharmacology
Inhibitory Concentration 50
Metalloendopeptidases / antagonists & inhibitors*
Metalloendopeptidases / metabolism
Piperazine / chemistry*
Plasmodium falciparum / drug effects
Plasmodium falciparum / enzymology
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology
Protozoan Proteins / antagonists & inhibitors*
Protozoan Proteins / metabolism
Structure-Activity Relationship

Substances

Antimalarials
Hydroxamic Acids
Protease Inhibitors
Protozoan Proteins
Piperazine
Metalloendopeptidases
falcilysin protein, Plasmodium falciparum