Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors

The identification of a new series of growth inhibitors of Trypanosoma cruzi, the causative agent of Chagas' disease, is described. In vitro screening of a subset of compounds from our in-house compound collection against the parasite led to the identification of hit compound 1 with low micromolar inhibition of T. cruzi growth. SAR exploration on the hit compound led to the identification of compounds that show nanomolar parasite growth inhibition (T. cruzi EC; 50; ≤ 100 nM) and no cytotoxicity in human cells (HeLa CC; 50; > 50 μM). Further investigation identified CYP51 inhibition (compound 11 CYP51 IC; 50; 52 nM) as a possible mechanism of action of this new class of anti-parasitic agents.