Unambiguous synthesis and prophylactic antimalarial activities of imidazolidinedione derivatives.
WR182393, a guanidinoimidazolidinedione derivatives with potent causal prophylactic antimalarial activity by intramuscular injection, was previously prepared by treatment of chloroproguanil and diethyl oxalate, yielding a mixture of two closely related isomers. Poor solubility of the mixture made the separation and purification impossible. To overcome the separation problem, new and facile unambiguous syntheses of the two active components were reported. The new synthetic methods facilitate the synthesis of not only the active components, but also their derivatives. To search for compounds with good oral efficacy, a series of carbamate derivatives of the active components were prepared by the new procedure, many of which showed profound causal prophylactic antimalarial activity against Plasmodium yoelii in mouse by oral administration.
Zhang
Quan
Q
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
Guan
Jian
J
Sacci
John
J
Ager
Arba
A
Ellis
William
W
Milhous
Wilbur
W
Kyle
Dennis
D
Lin
Ai J
AJ
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000469:parasitology / Q000517:prevention & control; D008297:Male; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii; D013329:Structure-Activity Relationship
D000962:Antimalarials; D002219:Carbamates; D006146:Guanidines; D007093:Imidazoles; D048289:Imidazolidines; C073156:WR 182393