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

Background: Chagas disease is a neglected tropical disease that affects millions of people worldwide and for which no effective treatment is available. Materials & methods: 17 chalcones were synthesized, for which the inhibition of cruzain and trypanocidal activity were investigated. Results: Chalcone C8 showed the highest cruzain inhibitory (IC 50  = 0.536 μm) and trypanocidal activity (IC 50  = 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 2  = 0.786; r 2  = 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. Conclusion: These results demonstrate that these chalcones are worthwhile hits to be further optimized in Chagas disease drug discovery programs.