Design, synthesis and biological evaluation of novel thiosemicarbazones as cruzipain inhibitors

Based on the activity of 23 TSCs on CZ taken from the literature, we have developed a QSAR model for predicting the activity of TSCs. New TSCs were designed and then tested against CZP, resulting in inhibitors with IC50 values in the nanomolar range. The modelling of the corresponding TSC-CZ complexes by molecular docking and QM/ QM ONIOM refinement indicates a binding mode compatible with what was expected for active TSCs, according to a geometry-based theoretical model previously developed by our research group. Kinetic experiments on CZP suggest that the new TSCs act by a mechanism that involves the formation of a reversible covalent adduct with slow association and dissociation kinetics. These results demonstrate the strong inhibitory effect of the new TSCs and the benefit of the combined use of QSAR and molecular modelling techniques in the design of new and potent CZ/CZP inhibitors.

Automated summary

Based on literature data, a QSAR model was developed to predict the activity of TSCs. New TSCs were designed and tested against CZP, resulting in highly potent inhibitors. Molecular docking and QM/QM ONIOM refinement studies confirmed the expected binding mode for the active TSCs. Kinetic experiments showed that the new TSCs act through the formation of a reversible covalent adduct. These findings highlight the effectiveness of QSAR and molecular modeling techniques in the design of potent CZ/CZP inhibitors.