title: Flavones as isosteres of 4(1H)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds.
abstract: Malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi-resistant strains of Plasmodium falciparum poses a great challenge to controlling the disease. A diverse set of flavones, isosteric to 4(1H)-quinolones, were prepared and profiled for their antiplasmodial activity against the blood stage of P. falciparum W2 strain, and the liver stage of the rodent parasite Plasmodium berghei. Ligand efficient leads were identified as dual stage antimalarials, suggesting that scaffold optimization may afford potent antiplasmodial compounds.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal. Electronic address: tiago.rodrigues@pharma.ethz.ch.
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.forename: Ana S
authors.initials: AS
authors.lastname: Ressurreição
authors.forename: Filipa P
authors.initials: FP
authors.lastname: da Cruz
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Marta P
authors.initials: MP
authors.lastname: Carrasco
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonçalves
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Daniel J V A
authors.initials: DJ
authors.lastname: dos Santos
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Francisca
authors.initials: F
authors.lastname: Lopes
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D015363:Quinolones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D047309:Flavones; D008024:Ligands; D015363:Quinolones
keywords: 1,8-diazabicycloundec-7-ene; CQ; DBU; DMF; Dual stage inhibitor; EEF; Flavone; LE; Ligand efficiency; Malaria; N,N-dimethylformamide; N-bromosuccinimide; NBS; PfNDH2; Plasmodium falciparum NADH:ubiquinone oxidoreductase; SAR; chloroquine; exo-erythrocytic form; ligand efficiency; structure–activity relationships