Flavones as isosteres of 4(1H)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds

  • Eur J Med Chem. 2013 Nov:69:872-80. doi: 10.1016/j.ejmech.2013.09.008.
Tiago Rodrigues  1 ,  Ana S Ressurreição ,  Filipa P da Cruz ,  Inês S Albuquerque ,  Jiri Gut ,  Marta P Carrasco ,  Daniel Gonçalves ,  Rita C Guedes ,  Daniel J V A dos Santos ,  Maria M Mota ,  Philip J Rosenthal ,  Rui Moreira ,  Miguel Prudêncio ,  Francisca Lopes
Affiliations
  • 1. 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: [email protected].
PMID: 24125849 DOI: 10.1016/j.ejmech.2013.09.008
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.

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.