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

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.

Marta P. Carrasco*[a, h], Marta Machado [b], Lídia Gonçalves [a], Moni Sharma [a], Jiri Gut [c], Amanda K. Lukens [d, e], Dyann F. Wirth [d, e], Vânia André [f], Maria Teresa Duarte [f], Rita C. Guedes [a], Daniel J. V. A. dos Santos [a, i], Philip J. Rosenthal [c], Ralph Mazitschek [d, e, g], Miguel Prudêncio *[b], Rui Moreira [a]

[a] M. P. Carrasco, L. Gonçalves, M. Sharma, R. C. Guedes, D. J. V. A. dos Santos, R. Moreira Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa (Portugal)

[b] M. Machado, M. Prudêncio Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal)

[c] J. Gut, P. J. Rosenthal Department of Medicine, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, San Francisco CA 94110 (USA)

[d] A. K. Lukens, D. F. Wirth, R. Mazitschek The Broad Institute, Infectious Diseases Program, Cambridge, MA 02142 (USA)

[e] A. K. Lukens, D. F. Wirth, R. Mazitschek Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA 02115 (USA)

[f] V. André, M. T. Duarte Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa (Portugal)

[g] R. Mazitschek Center for System Biology, Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge Street, Boston, MA 02114 (USA)

[h] M. P. Carrasco Current address: Department of Chemistry and Molecular Biology, Universi- ty of Gothenburg, 412 96 Göteborg (Sweden)

[i] D. J. V. A. dos Santos Current address: LAQV@REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto (Portugal)


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