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.

Ferrocenyl Paclitaxel and Docetaxel Derivatives: Impact of an Organometallic Moiety on the Mode of Action of Taxanes

“…Other ferrocened erivatives, for example, ferrocifen, [31] ferroquine [32] and ferrocenyl-based antifungal agents [33] are thought to act by producing reactives pecies through aF enton-type reaction. The bioactivity of the synthesised compounds described here demonstrates that the ferrocenyl moiety has ap ositive impact on thea ctivity of at axanea s both an activatoro ftubulin polymerisation and an antiproliferative agent.…”

Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates

“…[27] As discussed earlier, 5a exhibited moderate activity against H. contortus and T. colubriformis,b ut ruthenocenyl analogue 9b is inactive. For example, we envisagedt hat the redox properties of the ferrocene/ferrocenium system in 5a might lead to the production of toxic ROS and thus improve antiparasitica ctivity of the organic drug.…”

Ferrocene‐substituted bis(ethynyl)anthracene compounds as anticancer agents

“…Several ferrocene compounds have so far been examined and screened as important candidates for pharmaceutics . From the anthracene point of view, azonafide belongs to a well‐known class of drugs .…”