Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential antitrypanosomal products.

Abstract

Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

• Authors: Stefanie Zimmermann, Gerda Fouché, Maria De Mieri, Yukiko Yoshimoto, Toyonobu Usuki, Rudzani Nthambeleni, Christopher J Parkinson, Christiaan van der Westhuyzen, Marcel Kaiser, Matthias Hamburger, Michael Adams
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 19 Issue 3 Pg. 3523-38 (Mar 21 2014) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 24662071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lactones
• Sesquiterpenes
• Trypanocidal Agents

Topics

• Animals
• Cell Line
• Disease Models, Animal
• Female
• Lactones (chemistry, pharmacology, toxicity)
• Mice
• Parasitic Sensitivity Tests
• Rats
• Sesquiterpenes (chemistry)
• Structure-Activity Relationship
• Trypanocidal Agents (chemistry, pharmacology, toxicity)
• Trypanosoma brucei rhodesiense (drug effects)
• Trypanosomiasis, African (drug therapy, parasitology)