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

Chiang, AN and Valderramos, JC and Balachandran, R and Chovatiya, RJ and Mead, BP and Schneider, C and Bell, SL and Klein, MG and Huryn, DM and Chen, XS and Day, BW and Fidock, DA and Wipf, P and Brodsky, JL (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorganic and Medicinal Chemistry, 17 (4). 1527 - 1533. ISSN 0968-0896

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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. © 2009 Elsevier Ltd. All rights reserved.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Chiang, AN
Valderramos, JC
Balachandran, R
Chovatiya, RJ
Mead, BP
Schneider, C
Bell, SL
Klein, MG
Huryn, DM
Chen, XS
Day, BW
Fidock, DA
Wipf, Ppwipf@pitt.eduPWIPF
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Date: 15 February 2009
Date Type: Publication
Journal or Publication Title: Bioorganic and Medicinal Chemistry
Volume: 17
Number: 4
Page Range: 1527 - 1533
DOI or Unique Handle: 10.1016/j.bmc.2009.01.024
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0968-0896
MeSH Headings: Adenosine Triphosphatases--antagonists & inhibitors; Adenosine Triphosphatases--metabolism; Amides--pharmacology; Animals; Antimalarials--pharmacology; Erythrocytes--parasitology; HSP70 Heat-Shock Proteins--antagonists & inhibitors; HSP70 Heat-Shock Proteins--metabolism; Humans; Malaria, Falciparum--drug therapy; Malaria, Falciparum--parasitology; Models, Molecular; Parasitic Sensitivity Tests; Plasmodium falciparum--drug effects; Plasmodium falciparum--metabolism; Pyrimidinones--pharmacology
Other ID: NLM NIHMS140539, NLM PMC2775490
PubMed Central ID: PMC2775490
PubMed ID: 19195901
Date Deposited: 18 Jun 2013 20:12
Last Modified: 22 Jun 2021 16:55


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