Novel trypanocidal thiophen-chalcone cruzain inhibitors: structure- and ligand-based studies.

Chagas disease is a neglected tropical disease that affects millions of people worldwide and for which no effective treatment is available. 17 chalcones were synthesized, for which the inhibition of cruzain and trypanocidal activity were investigated. Chalcone showed the highest cruzain inhibitory (IC = 0.536 μm) and trypanocidal activity (IC = 0.990 μm). Molecular docking studies showed interactions involving Asp161 and the thiophen group interacting with the S2 subsite. Furthermore, quantitative structure-activity relationship (q = 0.786; r = 0.953) and density functional theory studies were carried out, and a correlation between the lowest unoccupied molecular orbital surface and trypanocidal activity was observed. These results demonstrate that these chalcones are worthwhile hits to be further optimized in Chagas disease drug discovery programs.