In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

Malar J. 2018 Dec 19;17(1):482. doi: 10.1186/s12936-018-2615-8.


Background: Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.

Results: The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.

Conclusions: These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

Keywords: ADME predictions; Antimalarial drugs; Hydroxy-naphthoquinones; Isoprenoid pathway; Plasmodium falciparum.

MeSH terms

  • Aniline Compounds / pharmacokinetics
  • Aniline Compounds / pharmacology*
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Malaria, Falciparum / drug therapy
  • Metabolic Networks and Pathways / drug effects*
  • Naphthoquinones / pharmacokinetics
  • Naphthoquinones / pharmacology*
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / metabolism
  • Terpenes / metabolism*


  • Aniline Compounds
  • Antimalarials
  • Naphthoquinones
  • Terpenes