title: Sedaxicenes: potential new antifungal ferrocene-based agents?
abstract: Fungal infections are a group of diseases spread all over the world with an extremely high morbidity. Worryingly, although several pathogenic fungi were found to develop resistance towards traditional therapy, research towards the discovery of novel antimycotic agents is very limited. Considering the promising results obtained with the ferrocene-based drug candidates Ferroquine and Ferrocifen as antimalarial and anticancer drug candidates, respectively, we envisaged derivatizing the organic scaffold of a new broad-spectrum fungicide, namely sedaxane, with a ferrocenyl moiety in order to obtain new metal-based antifungal agents. The new ferrocenyl sedaxane derivatives called herein Sedaxicenes (, and ) were characterized using different analytical techniques and the structures were confirmed by X-ray crystallography. As expected for antimycotic agents, , and were found to have a low or even no toxicity towards human cells (IC50 > 100 μM). Interestingly, while the parent drug did not display any mycotoxicity (EC50 > 100 μM), complex was found to have some antifungal activity with an IC50 value of 43 μM under the same experimental conditions. In order to investigate the possible redox-mediated mode of action of , we synthesized the ruthenocene analogue of , namely . Ruthenocene is known to have a completely different electrochemical behaviour from ferrocene although both the compounds are isostructural. As anticipated, complex was found to induce an increase of the reactive oxygen species level in S. cerevisiae, contrary to its analogue and to the parent compound sedaxane.
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. riccardo.rubbiani@chem.uzh.ch gilles.gasser@chem.uzh.ch.
authors.forename: R
authors.initials: R
authors.lastname: Rubbiani
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. riccardo.rubbiani@chem.uzh.ch gilles.gasser@chem.uzh.ch.
authors.forename: O
authors.initials: O
authors.lastname: Blacque
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. riccardo.rubbiani@chem.uzh.ch gilles.gasser@chem.uzh.ch.
authors.forename: G
authors.initials: G
authors.lastname: Gasser
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D015195:Drug Design; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D000075163:Metallocenes; D008958:Models, Molecular; D008968:Molecular Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D005296:Ferrous Compounds; D000075163:Metallocenes; D017382:Reactive Oxygen Species; C004998:ferrocene