title: Malaria causal prophylactic activity of imidazolidinedione derivatives.
abstract: A series of acid-stable carboxamide derivatives of 2-guanidinoimidazolidinedione (5a-c and 6a-c) were prepared as potential malaria prophylactic and radical cure agents. The new compounds showed moderate to good causal prophylactic activity in mice infected with Plasmodium yoelii sporozoites. Three compounds were further tested for causal prophylactic activity in Rhesus monkeys infected with Plasmodium cynomolgi sporozoites, and all showed a delay in patency from 13 to 40 days at 30 mg/kg/day x 3 days by IM dosing. Two out of four compounds tested for radical curative activity in Rhesus showed cure at 30 mg/kg/day x 3 days. The other two compounds showed delay in relapse from 16 to 68 days. Conversion of new carboxamides (5 and 6) to s-triazine derivatives (7) was demonstrated in mouse and human microsomal preparations and in rat plasma. The results suggest the metabolites, s-triazine derivatives 7, may be the active species of the new carboxamides 5a-c and 6a-c prepared in this study.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Xihong
authors.initials: X
authors.lastname: Wang
authors.forename: Kirsten
authors.initials: K
authors.lastname: Smith
authors.forename: Arba
authors.initials: A
authors.lastname: Ager
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.forename: Wilbur K
authors.initials: WK
authors.lastname: Milhous
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kozar
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Magill
authors.forename: Ai J
authors.initials: AJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy* / Q000517:prevention & control*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D016789:Plasmodium cynomolgi / Q000187:drug effects; D010967:Plasmodium yoelii / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D006146:Guanidines; D048289:Imidazolidines