title: In vitro antiplasmodial activities of semisynthetic N,N'-spacer-linked oligomeric ergolines.
abstract: Starting from three monomeric ergolines (terguride 1, festuclavine 2, pergolide 3) N,N'-spacer-linked oligomeric derivatives were prepared using different aliphatic or arylalkyl spacers. The compounds have been evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive strain poW and the chloroquine-resistant clone Dd2 of Plasmodium falciparum. Additionally, the cytotoxic effects against mouse fibroblasts (NIH 3T3) in vitro, and human hepatocytes were evaluated. All monomers displayed only a weak antiplasmodial effect, but N-1,N-1'-spacer-linked dimerization substantially enhanced their antiplasmodial activity. The best activities were observed for compounds showing a distance of six carbon atoms between two monomers, which can be obtained by aliphatic or p-xylene linkers. The N-6,N-6'-spacer-linked depropylpergolide dimer 3i exhibited the highest antiplasmodial activity of all compounds tested (IC(50) values: 0.14 and 0.13 microM against poW and Dd2, respectively). Unfortunately, it displayed toxic effects against the mouse fibroblast cell line NIH 3T3 (IC(50): 0.1+/-0.09 microM) and also against human hepatocytes at 100 microM (LDH-leakage: 15.58+/-0.87 microkat/L; GSH-level: 8.15+/-0.78 nmol/10(6) cells). However, the N-1,N-1'-spacer-linked trimer of festuclavine (2f), and also the N-1,N-1'-spacer-linked tetramer of terguride (1g) possessed remarkable antiplasmodial activities (IC(50): 0.54 and 1.53 microM, respectively, against Dd2) lacking cytotoxicity.
authors.affiliation: Institut für Pharmazie (Pharmazeutische Biologie), Freie Universität Berlin, Königin-Luise-Str. 2-4, D-14195 Berlin, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Jenett-Siems
authors.forename: Inga
authors.initials: I
authors.lastname: Köhler
authors.forename: Carola
authors.initials: C
authors.lastname: Kraft
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Pertz
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kren
authors.forename: Anna
authors.initials: A
authors.lastname: Fiserová
authors.forename: Marek
authors.initials: M
authors.lastname: Kuzma
authors.forename: Jitka
authors.initials: J
authors.lastname: Ulrichová
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bienzle
authors.forename: Eckart
authors.initials: E
authors.lastname: Eich
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004873:Ergolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D004873:Ergolines