Antitrypanosomal activity of triterpenoids and sterols from the leaves of Strychnos spinosa and related compounds.

Fractionation of an antitrypanosomal lipophilic leaf extract from Strychnos spinosa led to the isolation of eight triterpenoids and sterols in this plant part for the first time. Two of these were found to possess in vitro antitrypanosomal activity, namely, saringosterol (14) and 24-hydroperoxy-24-vinylcholesterol (15), with IC(50) values of 7.8 +/- 1.2 and 3.2 +/- 1.2 microM, respectively. The latter compound was isolated from a plant source for the first time. A comparative study on the antitrypanosomal activity of the isolated triterpenoids and sterols and some related compounds has indicated that the presence of an oxygenated function at C-28 or an oxygenated side chain at C-17 seems to be important for the antitrypanosomal activity of triterpenoids and sterols, respectively.

Antitrypanosomal compounds from the leaf essential oil of Strychnos spinosa.

The composition of the essential oil obtained by hydrodistillation of the leaves of Strychnos spinosa (Loganiaceae) was analysed by GC-FID and GC-MS. Out of twenty-two compounds identified in the oil, the main constituents were palmitic acid (34.3%), linalool (16.0%), and (E)-phytol (6.7%). Since the leaves of this plant are used in African traditional medicine to treat African trypanosomiasis, we evaluated the in vitro activity of the essential oil as well as of 15 of its components on Trypanosoma brucei brucei bloodstream forms and on mammalian cells (J774 murine macrophages) to evaluate the selectivity of the antitrypanosomal effect. The essential oil was active on the parasites without a great selectivity [IC50 on T. b. brucei = 13.5 microg/mL with a selectivity index (SI) of 4.4]. (E)-Nerolidol, a minor component of the hydrodistillate, as well as linalool, were shown to have a more potent and selective effect on the trypanosomes [IC50 = 1.7 and 2.5 microg/mL (7.6 and 16.3 microM) with SI = 35.7 and > 40, respectively]. These two oxygenated terpenes have promising activity and it would be of interest to study their mechanism of action as well as their in vivo activity.

Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases.

Cassytha filiformis (Lauraceae), a widely distributed parasitic plant, contains several aporphine alkaloids and is often used in African folk medicine to treat cancer, African trypanosomiasis and other diseases. In a previous investigation, we showed that the alkaloid plant extract and the isolated aporphines possessed in vitro cytotoxic properties. In this paper, we evaluated the in vitro activity of the alkaloid extract (IC50 = 2.2 microg/mL) and its three major aporphine alkaloids (actinodaphnine, cassythine, and dicentrine) on Trypanosoma brucei brucei as well as four related commercially available aporphines (bulbocapnine, glaucine, isocorydine, boldine). Only the three alkaloids from Cassytha filiformis were active on the trypanosomes in vitro (IC50 = 3-15 microM). Additionally, we compared the cytotoxicity of these seven compounds on HeLa cells. Glaucine was the most cytotoxic compound on HeLa cells (IC50 = 8.2 microM) in the series. In order to elucidate their mechanism of action, the binding mode of these molecules to DNA was studied by UV absorption, circular and linear dichroism spectroscopy. The results of the optical measurements indicated that all seven aporphines effectively bind to DNA and behave as typical intercalating agents. Biochemical experiments showed that actinodaphnine, cassythine and dicentrine also interfere with the catalytic activity of topoisomerases in contrast to the four other aporphines. These interactions with DNA may explain, at least in part, the effects observed on cancer cells and on trypanosomes.

Natural products active against African trypanosomes: a step towards new drugs.

This review covers compounds with activity on African trypanosomes (mainly Trypanosoma brucei subsp.,T congolense and T vivax) isolated from natural sources and is organized according to the structure of the etabolites (alkaloids, phenolic derivatives, quinones, terpenes and other metabolites). The literature from he mid-1980s up to June 2003 is reviewed and 89 references are cited.

In vitro antitrypanosomal activity of ethnopharmacologically selected Beninese plants.

The in vitro antitrypanosomal activity of methylene chloride, methanol and aqueous extracts of the leaves and twigs of five plant species traditionally used in Benin for the treatment of sleeping sickness were evaluated on Trypanosoma brucei brucei and their selectivity was analysed on Leishmania mexicana mexicana and J774 macrophage-like murine cells. The results showed that the four most active extracts had MIC values < or =19 microg/ml (Hymenocardia acida twig and leaf, Strychnos spinosa leaf, Trichilia emetica leaf methylene chloride extracts). All these extracts had a lower activity on L. m. mexicana and J774 cells. Determination of the IC50 values of the methylene chloride leaf extracts on two strains of trypanosomes (T. b. brucei and T. b. rhodesiense) and two mammalian cell lines (L6 and J774 cells) showed that all extracts possessed some antitrypanosomal activity with IC50's ranging from 1.5 to 39 microg/ml. All were also toxic to the mammalian cells, but usually with higher IC50's. The only exception was the S. spinosa methylene chloride leaf extract which had no toxicity on J774 cells. Although tannins have been identified in most of the species studied, they could not be detected in the most active extracts, just as alkaloids. The presence of flavonoids and quinones may at least in part explain the observed activities of some of the active extracts.