Identification of an antimalarial synthetic trioxolane drug development candidate.
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.
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA. jvenners@unmc.edu
Jonathan L
JL
Vennerstrom
Sarah
S
Arbe-Barnes
Reto
R
Brun
Susan A
SA
Charman
Francis C K
FC
Chiu
Jacques
J
Chollet
Yuxiang
Y
Dong
Arnulf
A
Dorn
Daniel
D
Hunziker
Hugues
H
Matile
Kylie
K
McIntosh
Maniyan
M
Padmanilayam
Josefina
J
Santo Tomas
Christian
C
Scheurer
Bernard
B
Scorneaux
Yuanqing
Y
Tang
Heinrich
H
Urwyler
Sergio
S
Wittlin
William N
WN
Charman
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry*; D001682:Biological Availability; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D010084:Oxidation-Reduction; D010545:Peroxides; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000737:chemistry*; D012995:Solubility; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
D000962:Antimalarials; D037621:Artemisinins; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D012717:Sesquiterpenes; D013141:Spiro Compounds; C489136:arterolane; C031327:artemisinin