Cyclopalladated Complexes With Functionalized Diphosphanes as Promising Antifungal Scaffolds.

Invasive fungal infections, especially those caused by Candida spp., have been classified as a serious global threat. The emergence of species intrinsically resistant to current drugs, along with the increase in acquired resistance, places significant pressure on the need to develop novel and more effective antifungal agents. A limited number of studies have shown the potential of palladium organometallic complexes as promising antifungal alternatives. Although the mechanism of antifungal activity of these complexes remains unaddressed, the findings support the idea that designing palladium (II) complexes could represent the next generation of antifungals. In this work, we synthesized four cyclopalladated complexes, 1a, 1b, 2a, and 2b, from Schiff base-amine phosphanes and evaluated their antifungal potential. Specifically, we assessed their spectrum of activity against several medically relevant Candida spp., their capacity to overcome resistance to current antifungal drugs, antibiofilm properties, uptake by fungal cells, in vivo toxicity, and intracellular effects. The most promising complexes, 1b and 2b, induce strong oxidative stress and lipid peroxidation, inhibit lipolysis, and disrupt vacuole integrity. Moreover, the rational design of the complexes allowed us to infer important structure-activity relationships. Our findings highlight the potential of palladium complexes as promising scaffolds for future antifungal therapeutic strategies and open new horizons for further development.