Nickel N-heterocyclic carbene complexes based on xanthines: Synthesis and antifungal activity on Candida sp.

Invasive fungal diseases affect more than two million people worldwide. The increasing incidence of invasive fungal infections is the result of many factors, including an increase in the resistance to current drugs. As such, there is an urgent need to obtain new drugs that are efficient, selective, and able to overcome existing resistance mechanisms. Candida yeasts are responsible for more than 70% of all nosocomial invasive fungal diseases. In this work, we describe the synthesis of nickel (II)(NHC) complexes based on xanthines, by direct metalation of xanthinium salts with nickelocene NiCp₂to yield [NiCpI(NHC)] complexes. For methyl caffeine, a biscarbene complex [NiCp(NHC)₂]⁺is also formed, resulting from carbene dissociation from the corresponding monocarbene. [NiCpI(NHC)] complexes are active as antifungals for Candida yeasts and show toxicity for human cells (HeLa) that is dependent on the substitution of N7 of the xanthine moiety. The biscarbene complex 5[NiCp(NHC)₂]⁺is highly selective for Candida glabrata and shows very low toxicity for human cells, being a promising candidate for selective treatment of C. glabrata infections.