title: Synthesis and antimalarial activity of 2-guanidino-4-oxoimidazoline derivatives.
abstract: A series of 2-guanidino-4-oxoimidazoline (deoxo-IZ) derivatives was prepared and showed potent antimalarial activities in rodent and Rhesus models. Compound 8e, the most potent analogues of this series, is the first non-8-aminoqinoline antimalarial that demonstrated radical curative activity in non-human primate by oral route and showed causal prophylactic activity comparable to that of the commonly used clinical drugs in Rhesus monkeys infected with sporozoites of Plasmodium cynomolgi. The metabolic stability and metabolites profile indicated that the new deoxo-IZ derivatives (8) may act as prodrugs of the corresponding IZ (1 and 2) derivatives.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Liu
authors.forename: Xihong
authors.initials: X
authors.lastname: Wang
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kozar
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.forename: Michael T
authors.initials: MT
authors.lastname: O'Neil
authors.forename: Ai J
authors.initials: AJ
authors.lastname: Lin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048288:Imidazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy / Q000517:prevention & control; D051379:Mice; D010962:Plasmodium berghei; D016789:Plasmodium cynomolgi; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D006146:Guanidines; D048289:Imidazolidines; D048288:Imidazolines; C561232:N-(tert-butoxycarbonyl)-N'-(3,4-dichlorophenyl)-N''-(1-isopropyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)guanidine; D011355:Prodrugs