Cynaropicrin: the first plant natural product with in vivo activity against Trypanosoma brucei.

A screen of 1800 plant and fungal extracts with subsequent HPLC-based activity profiling was done to identify new antiprotozoal leads from nature. This led to the identification of cynaropicrin (1) from the herb CENTAUREA SALMANTICA L. (Asteraceae) as a potent IN VITRO inhibitor of TRYPANOSOMA BRUCEI RHODESIENSE. It preferentially inhibited T. B. RHODESIENSE (IC (50) of 0.3 µM) and T. BRUCEI GAMBIENSE (IC (50) of 0.2 µM), compared to TRYPANOSOMA CRUZI (IC (50) of 4.4 µM) and PLASMODIUM FALCIPARUM (IC (50) of 3.0 µM). Testing against melarsoprol- and pentamidine-resistant strains (IC (50)s of 0.3 µM and 0.1 µM, respectively) showed no cross-resistance. Intraperitoneal administration of 2 × 10 mg/kg body weight/day in the T. B. RHODESIENSE STIB 900 acute mouse model led to a 92 % reduction of parasitemia compared to untreated controls on day seven post-infection. Removal of the 2-hydroxymethyl-2-propenoyl moiety of cynaropicrin led to a loss of toxicity towards T. B. RHODESIENSE. Cytotoxicities against rat myoblasts (L6 cells), human colon adenocarcinoma cells, and murine peritoneal macrophages were measured, and selectivity indices of 7.8, 62, and 9.5 were determined. This is the first report of a plant natural product with potent IN VIVO activity against TRYPANOSOMA BRUCEI.

Zimmermann S ，Kaiser M ，Brun R ，Hamburger M ，Adams M ... -  《-》

Antiparasitic activities of two sesquiterpenic lactones isolated from Acanthospermum hispidum D.C.

Aerial parts of Acanthospermum hispidum D.C. are often used by traditional healers in Benin for various diseases and especially for malaria. To identify active compounds from extracts of Acanthospermum hispidum D.CV. leaves previously shown to possess antimalarial properties and analyse in vivo activity and toxicity of crude extracts. Compounds were isolated from aerial part of Acanthospermum hispidum D.C. and structurally elucidated using extensive spectroscopic analysis. Antiplasmodial activity was evaluated in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity and in vivo against Plasmodium berghei berghei by the 4-day suppressive test. Selectivity of extract and purified compounds on Plasmodium parasites were evaluated by using MTT test on J774 macrophage like murine cells and WI38 human normal fibroblasts and also against two other parasites: Trypanosoma brucei brucei and Leishmania mexicana mexicana. Acute and sub-acute toxicities of a crude extract were evaluated on mice. Two known sesquiterpenic lactones were isolated: 1 (15-acetoxy-8β-[(2-methylbutyryloxy)]-14-oxo-4,5-cis-acanthospermolide) and 2 (9α-acetoxy-15-hydroxy-8β-(2-methylbutyryloxy)-14-oxo-4,5-trans-acanthospermolide). 1 and 2 showed in vitro antiplasmodial activity against the chloroquine-sensitive strain (3D7) with IC(50) of 2.9±0.5 and 2.23±0.09μM respectively. Only 2 showed a high selectivity index (SI: 18.4) on Plasmodium compared to cytotoxicity against human fibroblasts cell line (WI38). 1 and 2 also showed interesting antiparasitic activities in vitro against Trypanosoma brucei brucei (IC(50) of 2.45±0.49 and 6.36±1.42μM respectively) and Leishmania mexicana mexicana (IC(50) of 0.94±0.05 and 2.54±0.19μM respectively). Furthermore, crude acidic water extract and fractions containing one of the two isolated compounds displayed a weak in vivo antimalarial activity against Plasmodium berghei berghei with a long half-life causing a delayed effect. In vivo acute (2000mg/kg) and sub-acute (1000mg/kg) toxicity tests on the crude acidic water extract did not show toxicity. Crude acidic water extract, fractions and pure isolated compounds from Acanthospermum hispidum showed promising in vitro antiplasmodial activity. Despite our study did not show in vivo acute and subacute toxicities of the crude acidic water extract, its weak in vivo antimalarial activity and the in vitro cytotoxicity of pure compounds and enriched extracts containing 1 and 2 indicate that the aerial parts of Acanthospermum hispidum should be used with caution for malaria treatments.

Ganfon H ，Bero J ，Tchinda AT ，Gbaguidi F ，Gbenou J ，Moudachirou M ，Frédérich M ，Quetin-Leclercq J ... -  《-》

Antitrypanosomal sesquiterpene lactones from Saussurea costus.

In the course of a larger screen of 1800 plant and fungal extracts, the ethyl acetate extract of Saussurea costus roots potently inhibited the growth of Trypanosoma brucei rhodesiense. Subsequent HPLC based activity profiling led to the identification of the sesquiterpene lactones arbusculin B (1), α-cyclocostunolide (2), costunolide (3), and dehydrocostuslactone (4). They were tested for in vitro antitrypanosomal activities and cytotoxicity alongside the structurally related sesquiterpene lactones parthenolide (5), zaluzanin D (6), and eupatoriopicrin (7), and had IC(50)s between 0.8 and 22 μM. Cytotoxic IC(50)s were from 1.6 to 19 μM, and selectivity indices from 0.5 to 6.5.

Julianti T ，Hata Y ，Zimmermann S ，Kaiser M ，Hamburger M ，Adams M ... -  《-》

Trypanocidal, leishmanicidal and cytotoxic effects of anthecotulide-type linear sesquiterpene lactones from Anthemis auriculata.

Karioti A ，Skaltsa H ，Kaiser M ，Tasdemir D ... -  《-》

Antiprotozoal screening of 60 South African plants, and the identification of the antitrypanosomal germacranolides schkuhrin I and II.

Two hundred and seven extracts were prepared from sixty plants from South Africa and screened for in vitro activity against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. For the 21 extracts which inhibited the growth of one or more parasites with more than 95 % at 10 µg/mL, the IC50 values against all four protozoal parasites and cytotoxic IC50 values against L6 myoblasts were determined. Amongst the most notable results are the activities of Psoralea pinnata (IC50 of 0.15 µg/mL), Schkuhria pinnata (2.04 µg/mL), and Vernonia mespilifolia (1.01 µg/mL) against Trypansoma brucei rhodesiense. HPLC-based activity profiling was used to identify the active constituents in the extracts, and the germacranolide sesquiterpene lactones schkuhrin I and II from S. pinnata, and cynaropicrin from V. mespilifolia were identified, with IC50 values of 0.9, 1.5, and 0.23 µM, respectively.

Mokoka TA ，Xolani PK ，Zimmermann S ，Hata Y ，Adams M ，Kaiser M ，Moodley N ，Maharaj V ，Koorbanally NA ，Hamburger M ，Brun R ，Fouche G ... -  《-》