Structure-activity relationships of β-chalcogenamines: synthesis, enzyme inhibition, molecular docking and QSAR studies

A series of β-chalcogenamines was efficiently prepared through decarboxylative ring-opening reactions of 2-oxazolidinones by organochalcogen nucleophiles. Docking studies were carried out to elucidate some key molecular interactions between these compounds and the binding site of the enzyme cruzain, a validated target for Chagas’ disease drug discovery. The most active compound (IC 50 = 0.640 µM) has the N-benzylethanamine group as substituent, with the establishment of hydrogen bonds between the amino group from the ligand and the aspartic acid-161 residue. A good correlation was observed between the IC 50 values and the binding energy obtained by the docking protocol using the GoldScore function. Kernel-based partial least square regression method was used to create 2D QSAR models to predict the cruzain inhibition. This model showed R2 = 0.80, Q2 = 0.82 and a low standard deviation. These models could be used to the design of more potent and selective cruzain inhibitors.