silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense

As a continuation of our earlier study on the in vitro antiprotozoal activity of 40 natural sesquiterpene lactones (STLs), we ex-tended the set of tested compounds from our laboratories to 59. On the basis of this extended data set, further enriched by litera-ture data for 10 compounds tested under the same conditions, our quantitative structure-activity relationship (QSAR) analyses for activity against T. brucei rhodesiense (etiologic agent of human African trypanosomiasis, or sleeping sickness) were contin-ued, and the QSARmodel thus obtained with 69 structures was used to predict the activity of a virtual library of 1,750 STL struc-tures. As a major result from these calculations, furanoheliangolide-type compounds, a subclass of STLs hitherto untested against T. brucei rhodesiense, were predicted to have an exceptionally high level of in vitro activity. Four representative com-pounds of this type, goyazensolide, 4,5-dihydro-2=,3=-epoxy-15-deoxygoyazensolide, budlein A, and 4,15-isoatriplicolide tiglate, were therefore tested. They displayed 50 % inhibitory concentrations (IC50s) of 0.07, 0.20, 0.07, and 0.015M, respectively, so that the in silico prediction was experimentally confirmed. 4,15-Isoatriplicolide tiglate is the most potent STL against T. b. rhod-esiense found. Furanoheliangolide STLs were thus identified as interesting leads against this parasite which deserve more de-tailed investigations. Infections with trypanosomatid parasites of the genera Trypano-soma and Leishmania are neglected diseases for which only few drug therapies exist, and these therapies are often complicated by severe adverse effects/high toxicity. Furthermore, problems asso