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. © Georg Thieme Verlag KG Stuttgart · New York.