title: 1,2-disubstituted ferrocenyl carbohydrate chloroquine conjugates as potential antimalarial agents.
abstract: This work presents a new family of organometallic antimalarial compounds consisting of ferrocene bearing a chloroquine-derived moiety as well as a 1,2;3,5-diisopropylidene glucofuranose moiety at a cyclopentadienyl scaffold in a 1,2-substitution pattern. The synthetic route proceeds via a stereoselective functionalization of ferrocene carboxaldehyde to the 1,2-disubstituted conjugates. After complete characterization of these new, trifunctional conjugates, they were examined for their cytotoxicity in two cancerous cell lines (MDA-MB-435S and Caco2) and one non-cancerous cell line (MCF-10A), showing that increased cytotoxicity can be observed for the chloroquine ferrocenyl conjugates compared to their carbohydrate-substituted precursors. The antiplasmodial activity of the conjugates in a chloroquine-sensitive strain of Plasmodium falciparum (D10) and a chloroquine-resistant strain (Dd2) was determined. Monosubstituted conjugates 13, 14 and 15 exhibit decreasing activity with increasing alkyl chain length between the ferrocene and quinoline moiety, bifunctional conjugates 16, 17, 18 show constant activity, performing better than chloroquine in the Dd2 strain.
authors.affiliation: Advanced Applied Physics Solutions, Vancouver, BC, Canada.
authors.forename: Christoph
authors.initials: C
authors.lastname: Herrmann
authors.forename: Paloma F
authors.initials: PF
authors.lastname: Salas
authors.forename: Brian O
authors.initials: BO
authors.lastname: Patrick
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Adam
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D005296:Ferrous Compounds / Q000737:chemistry*; D006801:Humans; D000075163:Metallocenes; D009005:Monosaccharides / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; D009005:Monosaccharides; D002738:Chloroquine; C004998:ferrocene