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

Stefanie Zimmermann, Gerda Fouche, Maria De Mieri, Yukiko Yoshimoto, Toyonobu Usuki, Rudzani Nthambeleni, Christopher Parkinson, Christiaan van der Westhuyzen, Marcel Kaiser, Matthias Hamburger, Michael Adams

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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.
Original languageEnglish
Pages (from-to)3523-3538
Number of pages16
JournalMolecules
Volume19
Issue number3
DOIs
Publication statusPublished - Mar 2014

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    Zimmermann, S., Fouche, G., Mieri, M. D., Yoshimoto, Y., Usuki, T., Nthambeleni, R., Parkinson, C., Westhuyzen, C. V. D., Kaiser, M., Hamburger, M., & Adams, M. (2014). Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential anti-trypanosomal products. Molecules, 19(3), 3523-3538. https://doi.org/10.3390/molecules19033523