Diaminomaleonitrile derivatives as new potential antichagasic compounds: a study of structure–activity relationships

Schiff bases are synthetically accessible compounds that have been used in medicinal chemistry. In this work, 27 Schiff bases derived from diaminomaleonitrile were synthesized in high yields (80–98%). Molecular docking studies suggested that the Schiff bases interact with the catalytic site of cruzain. The most active cruzain inhibitor, analog (IC = 263 nM), was predicted to form an additional hydrophobic contact with Met68 in the binding site of the enzyme. A strong correlation between the IC values and ChemScore binding energies was observed (R = 0.99). Kernel-based 2D quantitative structure–activity relationship models for the whole dataset yielded sound correlation coefficients (R = 0.844; Q = 0.719). These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs.