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ChemMedChem. 2016 Oct 6;11(19):2194-2204. doi: 10.1002/cmdc.201600327. Epub 2016 Aug 19.

Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites.

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal. marta.carrasco@chem.gu.se.
2
Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Göteborg, Sweden. marta.carrasco@chem.gu.se.
3
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.
4
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
5
Department of Medicine, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, San Francisco, CA, 94110, USA.
6
The Broad Institute, Infectious Diseases Program, Cambridge, MA, 02142, USA.
7
Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
8
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal.
9
LAQV@REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Portugal.
10
Center for System Biology, Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge Street, Boston, MA, 02114, USA.
11
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. mprudencio@medicina.ulisboa.pt.

Abstract

The potential of azaaurones as dual-stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine-resistant Plasmodium falciparum strain and the liver stage of P. berghei, yielding compounds with dual-stage activity and sub-micromolar potency against erythrocytic parasites. Studies with genetically modified parasites, using a phenotypic assay based on the P. falciparum Dd2-ScDHODH line, which expresses yeast dihydroorotate dehydrogenase (DHODH), showed that one of the azaaurone derivatives has the potential to inhibit the parasite mitochondrial electron-transport chain. The global urgency in finding new therapies for malaria, especially against the underexplored liver stage, associated with chemical tractability of azaaurones, warrants further development of this chemotype. Overall, these results emphasize the azaaurone chemotype as a promising scaffold for dual-stage antimalarials.

KEYWORDS:

antiprotozoal agents; azaaurones; erythrocytic stage; liver stage; malaria

PMID:
27538856
DOI:
10.1002/cmdc.201600327
[Indexed for MEDLINE]

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