Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

Annette N. Chiang, Juan Carlos Valderramos, Raghavan Balachandran, Raj J. Chovatiya, Brian P. Mead, Corinne Schneider, Samantha L. Bell, Michael G. Klein, Donna M. Huryn, Xiaojiang S. Chen, Billy W. Day, David A. Fidock, Peter Wipf, Jeffrey L. Brodsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.

Original languageEnglish (US)
Pages (from-to)1527-1533
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number4
DOIs
StatePublished - Feb 15 2009
Externally publishedYes

Keywords

  • ATPase
  • Hsp40
  • Hsp70
  • J domain
  • Molecular chaperone
  • Pyrimidinone

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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