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Some 1,3-diarylureas and 1-((1,4- trans )−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also affecting the phosphorylation of eIF2 alpha subunit (eIF2α), we tested 25 analogs of 1,3-diarylureas and cHAUs against  Trypanosoma cruzi , the agent of Chagas disease. One of them (I-17) presented selectivity close to 10-fold against the insect replicative forms and also inhibited the multiplication of  T. cruzi  inside mammalian cells with an EC 50  of 1–3 µM and a selectivity of 17-fold. I-17 also prevented replication of African trypanosomes ( Trypanosoma brucei  bloodstream and procyclic forms) at similar doses. It caused changes in the  T. cruzi  morphology, arrested parasite cell cycle in G1 phase, and promoted phosphorylation of eIF2α with a robust decrease in ribosome association with mRNA. The activity against  T. brucei  also implicates eIF2α phosphorylation, as replacement of WT-eIF2α with a non-phosphorylatable eIF2α, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2α phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases.

Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation