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

Gary H. Posner, Wonsuk Chang, Lindsey Hess, Lauren Woodard, Sandra Sinishtaj, Aimee R. Usera, William Maio, Andrew S. Rosenthal, Alvin S. Kalinda, John G. D'Angelo, Kimberly S. Petersen, Remo Stohler, Jacques Chollet, Josefina Santo-Tomas, Christopher Snyder, Matthias Rottmann, Sergio Wittlin, Reto Brun, Theresa A. Shapiro

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1035-1042
Number of pages8
JournalJournal of medicinal chemistry
Volume51
Issue number4
DOIs
StatePublished - Feb 28 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Posner, G. H., Chang, W., Hess, L., Woodard, L., Sinishtaj, S., Usera, A. R., Maio, W., Rosenthal, A. S., Kalinda, A. S., D'Angelo, J. G., Petersen, K. S., Stohler, R., Chollet, J., Santo-Tomas, J., Snyder, C., Rottmann, M., Wittlin, S., Brun, R., & Shapiro, T. A. (2008). Malaria-infected mice are cured by oral administration of new artemisinin derivatives. Journal of medicinal chemistry, 51(4), 1035-1042. https://doi.org/10.1021/jm701168h