Newly Developed Drug Demonstrates Potent, Selective Activity Against Trypanosomatid Parasites

Using a plant-based compound, scientists have developed a semi-synthetic drug that, upon testing on infected mammalian cells in culture, showed highly effective activity against two parasites from the trypanosomatid family: Leishmania donovani, a cause of visceral leishmaniasis, and Trypanosoma cruzi, cause of Chagas disease.

There are significant drawbacks for currently available therapeutic drugs for both diseases, indicating an urgent need for more effective and safer drugs. Plant- or marine-derived natural compounds are promising sources. For example, the abietane-type diterpenoids (AtDs) present in plants exhibit a wide range of biological activities including anti-inflammatory, antibacterial, antifungal, and antimalarial properties. A few AtDs have shown promising activity against parasites in the trypanosomatid family.

In the new study, an international team led by researchers at VTT Technical Research Centre of Finland Ltd. (Espoo, Finland) prepared a small library of AtD amides, using commercially available dehydroabietylamine (C-1) as a starting material, and evaluated activity of the new compounds against L. donovani and T. cruzi. Other researchers in the collaboration were from University of Helsinki (Helsinki, Finland), Hebrew University-Hadassah Medical School (Jerusalem, Israel), and Swiss Tropical and Public Health Institute (Basel, Switzerland).

From the library screening, the compound C-10, an amide built from dehydroabietylamine and acrylic acid, was found to be highly potent against both parasites. Against L. donovani axenic amastigotes, C-10 displayed an IC50=0.37 μM and an outstanding selectivity index (SI)=63. SI values of 20 or higher are considered “hit activity criteria for protozoa” when screening for new bioactive compounds. Moreover, C-10 fully inhibited the growth of intracellular L. donovani amastigotes in human macrophages (from monocyte cell line THP-1), with IC50=0.06 μM. C-10 was also highly effective against T. cruzi amastigotes in rat myoblast L6 cells (IC50=0.6 μM; SI=58), being 3.5 times more potent than the reference compound benznidazole. Cytotoxicity of C-10 for macrophages and rat myoblast L6 cells was also tested and found to be relatively low.

C-10 was one of only two library compounds that possess physicochemical properties allowing them to efficiently cross the cell membranes and effectively kill parasites residing inside the host cells, reflecting their potential to act at the relevant stages responsible for disease. Interestingly, C-10 showed 6-fold more potent activity against L. donovani in infected macrophages than against axenic amastigotes.

Overall, the work highlights C-10 as an important compound for further investigation and development in pursuit of better drugs for patients suffering from leishmaniasis and Chagas disease.

The study, by Pirttimaa M et al., was published on February 26, 2016, in ACS’s Journal of Natural Products.

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VTT Technical Research Centre of Finland Ltd.