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

ChemMedChem
Authors
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.

Year of Publication
2016
Journal
ChemMedChem
Volume
11
Issue
19
Pages
2194-2204
Date Published
2016 Oct 06
ISSN
1860-7187
DOI
10.1002/cmdc.201600327
PubMed ID
27538856
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