Antiapicoplast and gametocytocidal screening to identify the mechanisms of action of compounds within the malaria box

Antimicrob Agents Chemother. 2014;58(2):811-9. doi: 10.1128/AAC.01500-13. Epub 2013 Nov 18.


Malaria remains a significant infectious disease that causes millions of clinical cases and >800,000 deaths per year. The Malaria Box is a collection of 400 commercially available chemical entities that have antimalarial activity. The collection contains 200 drug-like compounds, based on their oral absorption and the presence of known toxicophores, and 200 probe-like compounds, which are intended to represent a broad structural diversity. These compounds have confirmed activities against the asexual intraerythrocytic stages of Plasmodium falciparum and low cytotoxicities, but their mechanisms of action and their activities in other stages of the parasite's life cycle remain to be determined. The apicoplast is considered to be a promising source of malaria-specific targets, and its main function during intraerythrocytic stages is to provide the isoprenoid precursor isopentenyl diphosphate, which can be used for phenotype-based screens to identify compounds targeting this organelle. We screened 400 compounds from the Malaria Box using apicoplast-targeting phenotypic assays to identify their potential mechanisms of action. We identified one compound that specifically targeted the apicoplast. Further analyses indicated that the molecular target of this compound may differ from those of the current antiapicoplast drugs, such as fosmidomycin. Moreover, in our efforts to elucidate the mechanisms of action of compounds from the Malaria Box, we evaluated their activities against other stages of the life cycle of the parasite. Gametocytes are the transmission stage of the malaria parasite and are recognized as a priority target in efforts to eradicate malaria. We identified 12 compounds that were active against gametocytes with 50% inhibitory concentration values of <1 μM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Apicoplasts / drug effects*
  • Apicoplasts / metabolism
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Drug Discovery
  • Erythrocytes / drug effects
  • Erythrocytes / parasitology
  • Fosfomycin / analogs & derivatives
  • Fosfomycin / pharmacology
  • Hemiterpenes / antagonists & inhibitors*
  • Hemiterpenes / biosynthesis
  • High-Throughput Screening Assays
  • Humans
  • Inhibitory Concentration 50
  • Life Cycle Stages / drug effects*
  • Life Cycle Stages / physiology
  • Oligopeptides / pharmacology
  • Organophosphorus Compounds / antagonists & inhibitors*
  • Pipecolic Acids / chemistry
  • Pipecolic Acids / pharmacology*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • Antimalarials
  • Carbolines
  • Hemiterpenes
  • MMV008138
  • Oligopeptides
  • Organophosphorus Compounds
  • Pipecolic Acids
  • Small Molecule Libraries
  • Fosfomycin
  • isopentenyl pyrophosphate
  • fosmidomycin
  • epoxomicin