In SilicoPrediction and Experimental Evaluation of Furanoheliangolide Sesquiterpene Lactones as Potent Agents against Trypanosoma brucei rhodesiense

Abstract

ABSTRACTAs a continuation of our earlier study on thein vitroantiprotozoal activity of 40 natural sesquiterpene lactones (STLs), we extended the set of tested compounds from our laboratories to 59. On the basis of this extended data set, further enriched by literature data for 10 compounds tested under the same conditions, our quantitative structure-activity relationship (QSAR) analyses for activity againstT. brucei rhodesiense(etiologic agent of human African trypanosomiasis, or sleeping sickness) were continued, and the QSAR model thus obtained with 69 structures was used to predict the activity of a virtual library of 1,750 STL structures. As a major result from these calculations, furanoheliangolide-type compounds, a subclass of STLs hitherto untested againstT. brucei rhodesiense, were predicted to have an exceptionally high level ofin vitroactivity. Four representative compounds 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 0.015 μM, respectively, so that thein silicoprediction was experimentally confirmed. 4,15-Isoatriplicolide tiglate is the most potent STL againstT. b. rhodesiensefound. Furanoheliangolide STLs were thus identified as interesting leads against this parasite which deserve more detailed investigations.