title: Biological evaluation of hydroxynaphthoquinones as anti-malarials.
abstract: BACKGROUND
  The hydroxynaphthoquinones have been extensively investigated over the past 50 years for their anti-malarial activity. One member of this class, atovaquone, is combined with proguanil in Malarone®, an important drug for the treatment and prevention of malaria.
  
  
  METHODS
  Anti-malarial activity was assessed in vitro for a series of 3-alkyl-2-hydroxy-1,4-naphthoquinones (N1-N5) evaluating the parasitaemia after 48 hours of incubation. Potential cytotoxicity in HEK293T cells was assessed using the MTT assay. Changes in mitochondrial membrane potential of Plasmodium were measured using the fluorescent dye Mitrotracker Red CMXROS.
  
  
  RESULTS
  Four compounds demonstrated IC50s in the mid-micromolar range, and the most active compound, N3, had an IC50 of 443 nM. N3 disrupted mitochondrial membrane potential, and after 1 hour presented an IC50ΔΨmit of 16 μM. In an in vitro cytotoxicity assay using HEK 293T cells N3 demonstrated no cytotoxicity at concentrations up to 16 μM.
  
  
  CONCLUSIONS
  N3 was a potent inhibitor of mitochondrial electron transport, had nanomolar activity against cultured Plasmodium falciparum and showed minimal cytotoxicity. N3 may serve as a starting point for the design of new hydroxynaphthoquinone anti-malarials.
authors.forename: Desiree C
authors.initials: DC
authors.lastname: Schuck
authors.forename: Sabrina B
authors.initials: SB
authors.lastname: Ferreira
authors.forename: Laura N
authors.initials: LN
authors.lastname: Cruz
authors.forename: David R
authors.initials: DR
authors.lastname: da Rocha
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Moraes
authors.forename: Myna
authors.initials: M
authors.lastname: Nakabashi
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.forename: Celia R S
authors.initials: CR
authors.lastname: Garcia
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009285:Naphthoquinones / Q000494:pharmacology* / Q000633:toxicity; D009930:Organic Chemicals / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D005456:Fluorescent Dyes; D009285:Naphthoquinones; D009930:Organic Chemicals; C107472:red dye CMXRos