title: Discovery and preliminary structure-activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds.
abstract: Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC(50) 0.89 μM). Preliminary structure-activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC(50) 8.6 nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics.
authors.affiliation: School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Lydia P P
authors.initials: LP
authors.lastname: Liew
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Brent R
authors.initials: BR
authors.lastname: Copp
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C581733:1,14-spermine-di-(2-hydroxyphenylacetamide); D000081:Acetamides; D000962:Antimalarials; D013096:Spermine