Mechanistic and biological characterisation of novel <i>N</i> <sup>5</sup>-substituted paullones targeting the biosynthesis of trypanothione in <i>Leishmania</i>
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Trypanothione synthetase (TryS) produces <i>N</i> <sup>1</sup> <i>,N<sup>8</sup> </i>-bis(glutathionyl)spermidine (or trypanothione) at the expense of ATP. Trypanothione is a metabolite unique and essential for survival and drug-resistance of trypanosomatid parasites. In this study, we report the mechanistic and biological characterisation of optimised <i>N</i> <sup>5</sup>-substituted paullone analogues with anti-TryS activity. Several of the new derivatives retained submicromolar IC<sub>50</sub> against leishmanial TryS. The binding mode to TryS of the most potent paullones has been revealed by means of kinetic, biophysical and molecular modelling approaches. A subset of analogues showed an improved potency (EC<sub>50</sub> 0.5–10 µM) and selectivity (20–35) against the clinically relevant stage of <i>Leishmania braziliensis</i> (mucocutaneous leishmaniasis) and <i>L. infantum</i> (visceral leishmaniasis). For a selected derivative, the mode of action involved intracellular depletion of trypanothione. Our findings shed light on the molecular interaction of TryS with rationally designed inhibitors and disclose a new set of compounds with on-target activity against different <i>Leishmania</i> species.
