The activity, selectivity and pharmacological profile of imatinib derivates against Trypanosoma cruzi.

Abstract

Chagas disease (CD) is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi affecting more than 6 million people worldwide. Its treatment is based in old and toxic nitroderivative drugs necessitating for new alternatives. Imatinib (IMB) is a tyrosine kinase inhibitor used in cancer therapy, and previous reports demonstrate that some derivatives are active against T. cruzi justifying further synthesis screening of novel compounds derived from IMB. Our results demonstrate that all test derivatives are highly active against the intracellular forms of T. cruzi being similar or even more potent than the reference drug for CD - benznidazole (BZ). Besides, they were much more active than the parent molecule, displaying low EC₉₀ values (<10 µm) and good selectivity indexes (>10), which are relevant characteristics of a novel hit compound for CD therapy. However, when screened against bloodstream trypomastigotes, only 1 derivative, named PLDC 23/19, was as active (EC₅₀ = 18.8 µm) as BZ (EC₅₀ = 18.8 µm), while the others did not show activity up to 20 µm.