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

Abstract

dAs a continuation of our earlier study on the in vitro antiprotozoal 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 against T. 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 against T. brucei rhodesiense, were predicted to have an exceptionally high level of in vitro activity. 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 (IC 50 s) of 0.07, 0.20, 0.07, and 0.015 M, respectively, so that the in silico prediction was experimentally confirmed. 4,15-Isoatriplicolide tiglate is the most potent STL against T. b. rhodesiense found. Furanoheliangolide STLs were thus identified as interesting leads against this parasite which deserve more detailed investigations.

Anti-Trypanosomatid Elemanolide Sesquiterpene Lactones from Vernonia lasiopus O. Hoffm

“…The bioactivity data obtained in this study complements previous data on sesquiterpene lactones obtained in our lab. Elemanolide type sesquiterpene lactones have not previously been reported to have anti-trypanosomal activity, therefore that the data reported here also broaden the knowledge on structure–anti-trypanosomal activity relationships of sesquiterpene lactones [ 10 , 28 ].…”

“…Natural products from plants, microorganisms and marine organism have a long and successful tradition as drugs or as leads in drug development [ 7 , 8 ]. In continuation of our ongoing search for new anti-trypanosomal agents in plants [ 9 , 10 , 11 , 12 ], we set out to investigate the activity of Vernonia lasiopus O. Hoffm. (Asteraceae) and its secondary metabolites against protozoan parasites.…”

In Silico Studies Designed to Select Sesquiterpene Lactones with Potential Antichagasic Activity from an In‐House Asteraceae Database

“…For example, chemotaxonomic studies of the Asteraceae family have been performed using self‐organizing maps and neural networks, and QSAR studies have identified some sesquiterpene lactones with promising activities against infectious diseases, such as 4,15‐isoatripicolide tiglate, which was the most potent structure against T. brucei in a purely in silico study of 1750 SLs. This result was subsequently validated in an in vitro test (IC 50 =1.5 μ m ) . Some studies have shown how ligand‐based QSAR models complement structure‐based approaches by boosting the prediction performances when used in tandem; in addition, ligand‐based modeling has been used to select a more appropriate protein conformation for docking and assess the reliability of the docking experiment .…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…Sesquiterpene lactones (STLs) have been demonstrated to have potent and, in many instances, selective toxicity against protozoan parasites, the etiological agents of several neglected tropical diseases (NTDs). Recently, furanoheliangolide-type STLs, characterized by the presence of Michael-acceptor structural motifs, were demonstrated to be endowed with high-level in vitro activity against Trypanosoma brucei rhodesiense [55]. In their work, Lenz and colleagues [56] studied the molecular basis of the activity of different furanoheliangolides.…”