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Molecules 2014, 19(3), 3523-3538; doi:10.3390/molecules19033523

Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products

1
Department Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
2
Department Medical Parasitology & Infection Biology, Swiss TPH, Socinstrasse 57, 4000 Basel, Switzerland
3
CSIR Biosciences, Meiring Naudé Road, Brummeria, Pretoria 0001, Gauteng, South Africa
4
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda, Tokyo 102-8554, Japan
5
School of Biomedical Sciences, Charles Sturt University, Orange, NSW 2800, Australia
6
University of Basel, Petersplatz 1, 4003 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Received: 12 November 2013 / Revised: 13 March 2014 / Accepted: 13 March 2014 / Published: 21 March 2014
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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. View Full-Text
Keywords: cynaropicrin; sesquiterpene lactones; antitrypanosomal; cytotoxicity; structure-activity-relationship; dimethylamino analogues; T. b. rhodesiense acute mouse model cynaropicrin; sesquiterpene lactones; antitrypanosomal; cytotoxicity; structure-activity-relationship; dimethylamino analogues; T. b. rhodesiense acute mouse model
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Zimmermann, S.; Fouché, G.; De Mieri, M.; Yoshimoto, Y.; Usuki, T.; Nthambeleni, R.; Parkinson, C.J.; van der Westhuyzen, C.; Kaiser, M.; Hamburger, M.; Adams, M. Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products. Molecules 2014, 19, 3523-3538.

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