Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones

Abstract

Prompted by results of our previous studies where we found high activity of some sesquiterpene lactones (STLs) against Trypanosoma brucei rhodesiense (which causes East African sleeping sickness), we have now conducted a structure-(in-vitro)-activity study on a set of 40 STLs against T. brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. Furthermore, cytotoxic activity against L6 rat skeletal myoblast 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 0.05-0.1 µM, which is about 10 times lower than their cytotoxic activity). It was found that all investigated antiprotozoal activities are significantly correlated with cytotoxicity and the major determinants for activity are α,β-unsaturated structural elements, also known to be essential for other biological activities of STLs. It was observed, however, that certain compounds are considerably more toxic against protozoa than against mammalian cells while others are more cytotoxic than active against the protozoa. A comparative QSAR analysis was therefore undertaken, in order to discern the antiparasitic activity of STLs against T. brucei and cytotoxicity. Both activities were found to depend to a large extent on the same structural elements and molecular properties. The observed variance in the biological data can be explained in terms of subtle variations in the relative influences of various molecular descriptors.

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

“…Cnicin displayed high anti-parasitic activity against T. brucei rhodesiense (IC 50 = 1.3 lM), while alantolactone was moderately active against all the four pathogens (Schmidt et al, 2009).…”

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

“…At the same time, and possibly even more importantly, QSAR models may also be used for predictive purposes within certain bounds, i.e., they should allow activity predictions for compounds not previously tested and thus help rationalize compound selection for further testing. In the present study, we have extended and refined the previous QSAR model for anti-T. b. rhodesiense activity of STLs (7) and used it to predict the activities of a virtual library of 1,750 natural STLs in order to find representatives of hithertountested types of STLs that might show high antitrypanosomal activity. The predictions made on the basis of the present QSAR analysis were experimentally confirmed for four STLs of the furanoheliangolide type.…”

“…In previous studies, it was shown by our group (5)(6)(7)(8) and others (9-11) that sesquiterpene lactones (STLs) possess considerable activity especially against Trypanosoma brucei rhodesiense (etiologic agent of East African HAT). We previously presented quantitative structure-activity relationship (QSAR) models for a set of 40 STLs with respect to their antitrypanosomal and cytotoxic activities, and it was found that the underlying structure-activity relationships, although very similar, are not identical (7), indicating that a structural rationale for the selective activity of some compounds must exist.…”

Isolation of Two Isolates from Abrus precatorius Methanolic Extract Using Spectrometry

“…Terpenoids and furanoterpenes are responsible for in vitro activity against P. falciparum [36]. Aerucyclamides A-D is heterocyclic peptides and Citation: Saganuwan AS, Patrick AO, Ngozi JN, Reto B (2017) Isolation of Two Isolates from Abrus precatorius Methanolic Extract Using nostocarboline, an alkaloid respectively produced by Microcystis aeruginosa and Nostoc displayed activity against P. falciparum with a pronounced selectivity towards rat myoblasts [37]. Antiprotozoal activities are significantly correlated with cytotoxicity and the major determinants for activities are α and β-unsaturated and structural elements, also known to be essential for other biological activities of sesquiterpene lactones.…”