HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Why artemisinin and certain synthetic peroxides are potent antimalarials. Implications for the mode of action.

Abstract
The discovery that the sesquiterpene peroxide yingzhaosu A (13) and 1,2,4-trioxane artemisinin (14) are active against chloroquine-resistant strains of Plasmodium falciparum, has opened a new era in the chemotherapy of malaria. In vitro and in vivo tests with synthetic structurally simpler trioxanes clearly demonstrate that much of the skeleton of 14 is redundant and that chirality is not required for activity. In addition, structure-activity relations and the search for the pharmacophore reveal that high antimalarial activity can be displayed by molecules which do not resemble the geometry of 13 and 14 at all. The possible mode of action of 13, 14, and synthetic peroxides is examined. They are believed to kill intraerythrocytic Plasmodium by interacting with the heme discarded by proteolysis of ingested hemoglobin. Complexation of heme with the peroxide bond followed by electron transfer generates an oxy radical that evolves to the ultimate parasiticidal agent. Experiments with ferrous reagents indicate that active peroxides including 14 and its congeners kill the parasite by alkylation with a sterically non-encumbered C-centered radical. However, another possibility is the involvement of a Fe(IV)=O species as the toxic agent. The review covers our own and other contributions to this timely topic and evaluates the different mechanisms proposed for the mode of action of peroxidic antimalarials.
AuthorsC W Jefford
JournalCurrent medicinal chemistry (Curr Med Chem) Vol. 8 Issue 15 Pg. 1803-26 (Dec 2001) ISSN: 0929-8673 [Print] Netherlands
PMID11772352 (Publication Type: Journal Article, Review)
Chemical References
  • Antimalarials
  • Artemisinins
  • Peroxides
  • Sesquiterpenes
  • artemisinine
Topics
  • Animals
  • Antimalarials (chemistry, pharmacology, therapeutic use)
  • Artemisinins
  • Humans
  • Malaria (drug therapy, prevention & control)
  • Peroxides (pharmacology)
  • Plasmodium (drug effects)
  • Sesquiterpenes (chemistry, pharmacology, therapeutic use)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: