Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites

Sci Rep. 2021 Jan 22;11(1):2121. doi: 10.1038/s41598-021-81486-z.


The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Drug Evaluation, Preclinical / methods
  • Hep G2 Cells
  • High-Throughput Screening Assays / methods*
  • Humans
  • Liver / drug effects*
  • Liver / parasitology
  • Malaria, Falciparum / blood
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / parasitology
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / physiology
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / physiology
  • Protective Agents / chemistry
  • Protective Agents / pharmacology
  • Reproducibility of Results
  • Structure-Activity Relationship
  • Thiadiazines / chemistry
  • Thiadiazines / pharmacology


  • Antimalarials
  • Protective Agents
  • Thiadiazines