title: Probing the aurone scaffold against Plasmodium falciparum: design, synthesis and antimalarial activity.
abstract: A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003 Lisboa, Portugal.
authors.forename: Marta P
authors.initials: MP
authors.lastname: Carrasco
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003 Lisboa, Portugal.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Newton
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003 Lisboa, Portugal.
authors.forename: Lídia
authors.initials: L
authors.lastname: Gonçalves
authors.affiliation: Unidade de Microbiologia Molecular e Infecção, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Góis
authors.affiliation: Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1349-008 Lisboa, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Machado
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA 94143, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1349-008 Lisboa, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Nogueira
authors.affiliation: Unidade de Microbiologia Molecular e Infecção, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hänscheid
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003 Lisboa, Portugal.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003 Lisboa, 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, Box 0811, San Francisco, CA 94143, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003 Lisboa, Portugal. Electronic address: rmoreira@ff.ul.pt.
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects*; D014617:Vacuoles / Q000187:drug effects
chemical_list: D000962:Antimalarials; D001572:Benzofurans; C486837:aurone
keywords: Aurones; Cross-coupling reactions; Malaria; Plasmodium falciparum