Malaria-infected mice are cured by oral administration of new artemisinin derivatives

J Med Chem. 2008 Feb 28;51(4):1035-42. doi: 10.1021/jm701168h. Epub 2008 Jan 31.

Abstract

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6-7 postinfection. At only 3 x 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14-17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials.

Publication types

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

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Artemisinins / chemical synthesis*
  • Artemisinins / chemistry
  • Artemisinins / therapeutic use
  • Malaria / drug therapy*
  • Mice
  • Plasmodium berghei
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Artemisinins