title: Cynaropicrin: the first plant natural product with in vivo activity against Trypanosoma brucei.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zimmermann
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
authors.forename: Michael
authors.initials: M
authors.lastname: Adams
mesh_terms: D000818:Animals; D002460:Cell Line; D031179:Centaurea / Q000737:chemistry*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D035261:Plant Components, Aerial / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014347:Trypanosoma brucei gambiense / Q000187:drug effects; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology*
chemical_list: D007783:Lactones; D010936:Plant Extracts; D012717:Sesquiterpenes; D014344:Trypanocidal Agents; C075687:cynaropicrin