title: Malaria-infected mice are cured by oral administration of new artemisinin derivatives.
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.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218-2685, USA. ghp@jhu.edu
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
authors.forename: Wonsuk
authors.initials: W
authors.lastname: Chang
authors.forename: Lindsey
authors.initials: L
authors.lastname: Hess
authors.forename: Lauren
authors.initials: L
authors.lastname: Woodard
authors.forename: Sandra
authors.initials: S
authors.lastname: Sinishtaj
authors.forename: Aimee R
authors.initials: AR
authors.lastname: Usera
authors.forename: William
authors.initials: W
authors.lastname: Maio
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Rosenthal
authors.forename: Alvin S
authors.initials: AS
authors.lastname: Kalinda
authors.forename: John G
authors.initials: JG
authors.lastname: D'Angelo
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Petersen
authors.forename: Remo
authors.initials: R
authors.lastname: Stohler
authors.forename: Jacques
authors.initials: J
authors.lastname: Chollet
authors.forename: Josefina
authors.initials: J
authors.lastname: Santo-Tomas
authors.forename: Christopher
authors.initials: C
authors.lastname: Snyder
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D010962:Plasmodium berghei; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins