Antiprotozoal activity of sequiterpene lactones – modelling of biological target properties and quantitative structure-activity relationships

In continuation of earlier studies where we found a high activity of some sesquiterpene lactones (STL) against Trypanosoma brucei rhodesiense (causing East African sleeping sickness) [1, 2], we have now conducted a structure-activity study on a set of 39 STL against T. brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. Furthermore, cytotoxic activity against murine cells was assessed. Some of the compounds possess high activity, especially against T. brucei (e.g. helenalin and some of its esters with IC₅₀-values of 0.05–0.1µM which is about 10 times lower than their cytotoxic activity). The accumulated data clearly show that antiprotozoal activity is governed at least in part by different structural features than the cytotoxic effect against mammalian cells. In order to illuminate such factors underlying the observed selectivity, a QSAR study was conducted using the program Quasar [3]. This program constructs hypothetical surfaces of the presumed biological target based on the superimposed 3D molecular structures of the compounds. A Quasar model correlates the computed binding affinities of the ligands to the receptor surface with their experimental bioactivity data. Since the molecular mechanism underlying the studied activities is presumed to be related to covalent modification of the target by Michael addition, the standard setup of Quasar was modified by including the energy of each compound's lowest unoccupied molecular orbital (εLUMO) as a descriptor of electrophilic reactivity. Models of good to excellent descriptive and predictive quality could be obtained for the T. brucei and cytotoxicity data. Models for the other mentioned bioactivities are still under development.

Acknowledgements: Thanks to Dr. A Vedani, Biographics Laboratory 3R, Basel, Switzerland, for valuable discussions concerning Quasar and to C. Heitland and J. Mack, Münster, for conducting some of the calculations during an undergraduate research project.

References: [1] Schmidt TJ et al. (2002) Planta Med. 68: 750–751. [2] Nour AMM et al. (2006) Planta Med. 72: 1004–1005. [3] Vedani A, Dobler M. (2002) J. Med. Chem. 45: 2139–2149.