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Sedaxicenes: potential new antifungal ferrocene-based agents?


Rubbiani, Riccardo; Blacque, Olivier; Gasser, Gilles (2016). Sedaxicenes: potential new antifungal ferrocene-based agents? Dalton Transactions, 45(15):6619-6626.

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 (1a, 2 and 3) were characterized using different analytical techniques and the structures were confirmed by X-ray crystallography. As expected for antimycotic agents, 1a, 2 and 3 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 1a 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 1a, we synthesized the ruthenocene analogue of 1a, namely 1b. Ruthenocene is known to have a completely different electrochemical behaviour from ferrocene although both the compounds are isostructural. As anticipated, complex 1a was found to induce an increase of the reactive oxygen species level in S. cerevisiae, contrary to its 1b analogue and to the parent compound sedaxane.

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 (1a, 2 and 3) were characterized using different analytical techniques and the structures were confirmed by X-ray crystallography. As expected for antimycotic agents, 1a, 2 and 3 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 1a 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 1a, we synthesized the ruthenocene analogue of 1a, namely 1b. Ruthenocene is known to have a completely different electrochemical behaviour from ferrocene although both the compounds are isostructural. As anticipated, complex 1a was found to induce an increase of the reactive oxygen species level in S. cerevisiae, contrary to its 1b analogue and to the parent compound sedaxane.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2016
Deposited On:09 Feb 2017 15:17
Last Modified:10 Feb 2017 08:43
Publisher:Royal Society of Chemistry
ISSN:1477-9226
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1039/C5DT04231C

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