In vitro antiplasmodial activities of semisynthetic N,N′-spacer-linked oligomeric ergolines Original Research Article

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 (IC50 values: 0.14 and 0.13 μM against poW and Dd2, respectively). Unfortunately, it displayed toxic effects against the mouse fibroblast cell line NIH 3T3 (IC50: 0.1±0.09 μM) and also against human hepatocytes at 100 μM (LDH-leakage: 15.58±0.87 μkat/L; GSH-level: 8.15±0.78 nmol/106 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 (IC50: 0.54 and 1.53 μM, respectively, against Dd2) lacking cytotoxicity.