In search of patterns over physicochemical properties and pharmacological activities for a set of [MCl2(thiosemicarbazone)] complexes (M = Pt/Pd): Support for multiple mechanisms of antichagasic action excluding DNA-bonding in vivo?

In order to rationalize the available data related to the antichagasic activity of Pt/Pd complexes containing 5-nitrofurylthiosemicarbazones, in the present work we carried out a PCM/DFT comparative characterization of 16 Pt(II)/Pd(II) compounds of general formula [MCl2L] and the corresponding 5-nitrofurylthiosemicarbazone ligands (L) using multivariate techniques to sort and classify them and to search for patterns correlating the biological activity with calculated physicochemical descriptors. The data allow us to rationally propose that these compounds might act through dual or even multiple mechanisms of action, with preferred paths that depend on both the nature of metal and ligand. Moreover, these results suggest that the complexes in the set would not react in vivo with DNA, being biotransformed earlier, before gaining access to nuclear DNA in the cell. The binding mode and inhibitory potency of a selection of metal complexes and ligands with Trypanosoma cruzi cruzipain and trypanothione reductase enzymes is also modeled through molecular docking.

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► PCM/DFT characterization of sixteen antichagasic Pt(II)/Pd(II) complexes.
► Results suggest that these complexes would not react in vivo with DNA.
► A very good correlation between LUMO energy and redox potential is found.
► The antichagasic action of these species seems to be mediated by multiple mechanisms.