Structure identification and prophylactic antimalarial efficacy of 2-guanidinoimidazolidinedione derivatives.
The reported synthetic procedure of WR182393, a 2-guanidinoimidazolidinedione derivative with high prophylactic antimalarial activity, was found to be a mixture of three closely related products. Poor solubility of WR182393 in both water and organic solvents and its impractical synthetic method have made the purification and structure identification of the reaction mixture a highly challenging task. The problems were circumvented by prodrug approach involving carbamate formation of the mixture, which enhances the solubility of the mixture in common organic solvents and facilitates the separation and structure determination of the two products. The structures of the two components were determined by X-ray crystallography and NMR of their corresponding carbamates 3a and 4a. Additional alkyl carbamates were prepared according to the same approach and two new carbamates 3b and 4d were found to possess higher intramuscular (im) efficacy than the parent compound WR182393 against Plasmodium cynomolgi in Rhesus monkey.
Guan
Jian
J
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. jian.guan@na.amedd.army.mil
Zhang
Quan
Q
Montip
Gettayacamin
G
Karle
Jean M
JM
Ditusa
Charles A
CA
Milhous
Wilbur K
WK
Skillman
Donald R
DR
Lin
Ai J
AJ
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008958:Models, Molecular; D015394:Molecular Structure
D000962:Antimalarials; D006146:Guanidines; D007093:Imidazoles; C073156:WR 182393