title: Antimalarial polyamine analogues.
abstract: A series of novel tetraamines of the general formula RNH(CH2)xNH(CH2)yNH(CH2)xNHR was synthesized and examined for activity against growth of Plasmodium falciparum in vitro. Within the series, dibenzyl analogues (R = benzyl) were found to be the most effective growth inhibitors, with IC50 values of about 10(-6) M. Further modifications of the tetraamine provided the optimum chain length for antimalarial activity of y = 7, x = 3. Compound 8 (MDL 27,695) with the structure y = 7, x = 3, R = benzyl, in combination with the ornithine decarboxylase inhibitor alpha-(difluoromethyl)ornithine, resulted in radical cures when tested against experimental Plasmodium berghei infections in mice. The structure-activity relationships of the series are discussed.
authors.affiliation: Merrell Dow Research Institute, Cincinnati, Ohio 45215.
authors.forename: M L
authors.initials: ML
authors.lastname: Edwards
authors.forename: D M
authors.initials: DM
authors.lastname: Stemerick
authors.forename: A J
authors.initials: AJ
authors.lastname: Bitonti
authors.forename: J A
authors.initials: JA
authors.lastname: Dumont
authors.forename: P P
authors.initials: PP
authors.lastname: McCann
authors.forename: P
authors.initials: P
authors.lastname: Bey
authors.forename: A
authors.initials: A
authors.lastname: Sjoerdsma
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D011073:Polyamines / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011073:Polyamines; C058294:MDL 27695