title: 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.affiliation: 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.|Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Göteborg, Sweden. marta.carrasco@chem.gu.se.
authors.forename: Marta P
authors.identifier: 0000-0002-7775-2919
authors.initials: MP
authors.lastname: Carrasco
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Machado
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Lídia
authors.initials: L
authors.lastname: Gonçalves
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Moni
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, San Francisco, CA, 94110, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: The Broad Institute, Infectious Diseases Program, Cambridge, MA, 02142, USA.|Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Lukens
authors.affiliation: The Broad Institute, Infectious Diseases Program, Cambridge, MA, 02142, USA.|Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal.
authors.forename: Vânia
authors.initials: V
authors.lastname: André
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Duarte
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.|LAQV@REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Portugal.
authors.forename: Daniel J V A
authors.initials: DJ
authors.lastname: Dos Santos
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, San Francisco, CA, 94110, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: The Broad Institute, Infectious Diseases Program, Cambridge, MA, 02142, USA.|Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.|Center for System Biology, Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge Street, Boston, MA, 02114, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. mprudencio@medicina.ulisboa.pt.
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000469:parasitology*; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000469:parasitology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D056831:Coordination Complexes; C000620894:diruthenium-1
keywords: antiprotozoal agents; azaaurones; erythrocytic stage; liver stage; malaria