Identification of an antimalarial synthetic trioxolane drug development candidate

Nature. 2004 Aug 19;430(7002):900-4. doi: 10.1038/nature02779.

Abstract

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Artemisinins / chemistry*
  • Biological Availability
  • Drug Design*
  • Drug Evaluation, Preclinical*
  • Half-Life
  • Heterocyclic Compounds, 1-Ring / chemical synthesis*
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics
  • Heterocyclic Compounds, 1-Ring / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Malaria / drug therapy
  • Malaria / metabolism
  • Malaria / parasitology
  • Mice
  • Oxidation-Reduction
  • Peroxides*
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / physiology
  • Plasmodium falciparum / drug effects
  • Rats
  • Rats, Wistar
  • Sesquiterpenes / chemistry*
  • Solubility
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology*
  • Tissue Distribution

Substances

  • Antimalarials
  • Artemisinins
  • Heterocyclic Compounds, 1-Ring
  • Peroxides
  • Sesquiterpenes
  • Spiro Compounds
  • arterolane
  • artemisinin