Identification of indirubin derivatives as anti-trypanosomal agents

Abstract

Trypanosoma brucei has been identified as the parasite responsible for the sleeping sickness encountered in sub-Saharan Africa, resulting in severe damages in the central nervous system and various organs, and is life-threatening if not timely treated. The population at high and moderate risk of being infected rises to more than 20 million, whereas the lack of effective vaccines and the serious limitations of current chemotherapy, makes the discovery of new antiparasitics an urgent need. Indirubins represent a class of compounds offering great possibilities for the treatment of parasite infections like leishmaniasis, while their activity has been associated with the inhibition of parasitic kinases and specifically Leishmania donovani (Ld) GSK-3 s [1, 2]. In addition, the T. brucei l orthologue of GSK-3, TbGSK-3 s has been identified as a promising drug target as it is essential for parasite viability [3]. In this context, we proceeded to the screening of sixty-nine 5-, 6-, 7- and 5, 6- substituted indirubin derivatives in order to assess their antiparasitic potential against T. brucei bloodstream forms. Moreover, the inhibition of TbGSK-3 s was tested in combination with cytotoxicity on J774.1 murine macrophage cell line. Compound 1 showed a significant inhibitory activity towards trypanosomal GSK-3 while retaining low toxicity on macrophages, thus pointing to a new substitution pattern for indirubin derivatives to be further developed as antitrypanosomal agents.