Abstract
Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.
Highlights
Sleeping sickness, or human African trypanosomiasis (HAT), is a deadly protozoal disease caused by Trypanosoma brucei species spread by tsetse flies (Glossina spp.)
This study explores the antitrypanosomal structure-activity relationships within this compound class using a group of 18 molecules comprising natural sesquiterpene lactone (STL) and 16 semi-synthetic STL-amines and two other derivatives against T. b. rhodesiense in vitro
The in vitro antitrypanosomal activity of compounds 1–34 was determined against T. b. rhodesiense (STIB 900 strain), while their cytotoxicity was evaluated using rat myoblast L6 cells to determine the selectivity indices (SI; IC50 L6/IC50 T. b.) of each compound (Figure 1, Table 1)
Summary
Human African trypanosomiasis (HAT), is a deadly protozoal disease caused by Trypanosoma brucei species spread by tsetse flies (Glossina spp.). Gambiense (5% of cases), differ in terms of their geographic distribution, clinical pictures, and the drugs used to treat parasitemia [1]. There are about 30,000 new HAT cases annually, and as many as 30 million people live in HAT endemic areas [2]. Natural products from plants have been instrumental in developing drugs to treat protozoal diseases, such as quinine and artemisinin against malaria [5,6]. Though, no natural product-based antitrypanosomal drugs are in use or even in late stage clinical development. We reported the in vivo activity [7] and mode of action [8] of cynaropicrin (1), a natural sesquiterpene lactone (STL)
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