Fluorine Makes the Difference—Gold(I)‐NHC Complexes With Fluoroaryl Substituents Exhibit Highly Potent Antileishmanial Activity

A family of neutral gold(I) complexes involving N ‐heterocyclic carbene ligands bearing fluoro‐aryl groups has been synthesized and characterized in order to evaluate its antileishmanial activity in vitro for all complexes and in vivo for the hit 34 . Computational docking experiments on the potential target trypanothione reductase were performed for all complexes. Regarding complex 34 , trypanothione reductase inhibition, ROS formation, as well as the impact on target genes by RT‐qPCR have been addressed. Complex 34 showed almost identical activity in vitro, combined with higher selectivity than amphotericin B, the most effective drug currently used against leishmaniasis in clinical use. The high activity of this complex has been confirmed by in vivo experiments. Mechanistical studies reveal that gold complex 34 rapidly alters the expression of key genes involved in Leishmania infantum's redox homeostasis and mitochondrial function after treatment. The significant upregulation of genes in the trypanothione system suggests an early adaptive response to oxidative stress induced by this complex.