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 (IC₅₀ of 0.3 µM) and T. brucei gambiense (IC₅₀ of 0.2 µM), compared to Trypanosoma cruzi (IC₅₀ of 4.4 µM) and Plasmodium falciparum (IC₅₀ of 3.0 µM). Testing against melarsoprol- and pentamidine-resistant strains (IC₅₀s 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.

Key words

Centaurea salmantica L. - Asteraceae - antitrypanosomal - human African trypanosomiasis (HAT) - Trypanosoma brucei rhodesiense - sesquiterpene lactone - cynaropicrin

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