Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate

Nat Commun. 2015 Mar 31;6:6715. doi: 10.1038/ncomms7715.


The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.

Publication types

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

MeSH terms

  • Amines / pharmacology
  • Animals
  • Antimalarials / pharmacology*
  • Drug Evaluation, Preclinical
  • Drug Resistance, Microbial
  • Guinea Pigs
  • Half-Life
  • Plasmodium falciparum / drug effects*
  • Pyrimidines / pharmacology*
  • Rats


  • Amines
  • Antimalarials
  • Pyrimidines

Associated data

  • SRA/SRP052918