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

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2 Scopus citations

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.

Original languageEnglish
Pages (from-to)1846-1848
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number10
DOIs
StatePublished - Jun 1 2018

Keywords

  • Falcilysin
  • Hydroxamic acid
  • Malaria
  • Metalloprotease
  • Protease inhibitors

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    Chance, J. P., Fejzic, H., Hernandez, O., Istvan, E. S., Andaya, A., Maslov, N., Aispuro, R., Crisanto, T., Nguyen, H., Vidal, B., Serrano, W., Kuwahara, B., Pugne Andanado, C., Goldberg, D. E., & Mallari, J. P. (2018). Development of piperazine-based hydroxamic acid inhibitors against falcilysin, an essential malarial protease. Bioorganic and Medicinal Chemistry Letters, 28(10), 1846-1848. https://doi.org/10.1016/j.bmcl.2018.04.010