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

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.

• Authors: Marta P Carrasco, Marta Machado, Lídia Gonçalves, Moni Sharma, Jiri Gut, Amanda K Lukens, Dyann F Wirth, Vânia André, Maria Teresa Duarte, Rita C Guedes, Daniel J V A Dos Santos, Philip J Rosenthal, Ralph Mazitschek, Miguel Prudêncio, Rui Moreira
• Journal: ChemMedChem (ChemMedChem) Vol. 11 Issue 19 Pg. 2194-2204 (10 06 2016) ISSN: 1860-7187 [Electronic] Germany
• PMID: 27538856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antimalarials
• Coordination Complexes
• diruthenium-1

Topics

• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coordination Complexes (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Erythrocytes (drug effects, parasitology)
• HEK293 Cells
• Humans
• Liver (drug effects, parasitology)
• Molecular Structure
• Parasitic Sensitivity Tests
• Plasmodium berghei (drug effects, growth & development)
• Plasmodium falciparum (drug effects, growth & development)
• Structure-Activity Relationship