title: Synthesis and in vitro and in vivo evaluation of antimalarial polyamines.
abstract: We recently reported that 1,14-diphenylacetamide derivatives of spermine exhibit potent nM in vitro growth inhibition properties of Plasmodium falciparum. In an effort to expand the structure-activity relationship of this compound class towards malaria, we have prepared and biologically tested a library that includes benzamide and 3-phenylpropanamide 'capping acid' groups, and polyamines that include spermine (PA3-4-3) and chain extended analogues PA3-8-3 and PA3-12-3. 2-Hydroxy and 2,5-dimethoxy analogues were typically found to exhibit the most potent activity towards the dual drug resistant strain K1 of P. falciparum with IC50's in the range of 1.3-9.5 nM, and selectivity indices (SI) of 42,300 to 4880. In vivo evaluation of three analogues against Plasmodium berghei was undertaken, with one demonstrating a modest 27.9% reduction in parasitaemia.
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Lydia P P
authors.initials: LP
authors.lastname: Liew
authors.forename: A Norrie
authors.initials: AN
authors.lastname: Pearce
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Brent R
authors.initials: BR
authors.lastname: Copp
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011073:Polyamines
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