Malaria-infected mice are cured by oral administration of new artemisinin derivatives.
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.
Posner
Gary H
GH
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218-2685, USA. ghp@jhu.edu
Chang
Wonsuk
W
Hess
Lindsey
L
Woodard
Lauren
L
Sinishtaj
Sandra
S
Usera
Aimee R
AR
Maio
William
W
Rosenthal
Andrew S
AS
Kalinda
Alvin S
AS
D'Angelo
John G
JG
Petersen
Kimberly S
KS
Stohler
Remo
R
Chollet
Jacques
J
Santo-Tomas
Josefina
J
Snyder
Christopher
C
Rottmann
Matthias
M
Wittlin
Sergio
S
Brun
Reto
R
Shapiro
Theresa A
TA
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
D000962:Antimalarials; D037621:Artemisinins