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From Design to in Vivo Active Organometallic-Containing Antimycotic Agents
preprintsubmitted on 19.07.2020, 07:05 and posted on 20.07.2020, 12:02 by Riccardo Rubbiani, Tobias Weil, Noemi Tocci, Luciano Mastrobuoni, Severin Jeger, Marco Moretto, James Ng, Yan Lin, Jeannine Hess, Stefano Ferrari, Andres Kaech, Luke Young, John SPENCER, Anthony Moore, Kevin Cariou, Monica Borghi, Renga Giorgia, Luigina Romani, Gilles Gasser
Fungal infections are an alarming global problem, most importantly for immunocompromised patients in a hospital environment. The appearance of multidrug resistance in several fungal species is a strong indication that alternative treatments are required. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this work, by rational design, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (1a-4a). All compounds showed excellent in vitro activity against the yeast C. robusta, clearly surpassing the progenitor organic drug fluconazole. As anticipated, due to the presence of the ferrocenyl moiety in 1a-4a, a modest increase in ROS generation was observed on C. robusta upon treatment. Very importantly, enzyme inhibition and chemogenetic profiling demonstrated that lanosterol 14α-demethylase was the main target of the most active compound of the series, (N-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, 2a). Transmission electron microscopy (TEM) studies suggested that 2a induced a loss in wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of 2a was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, 2a showed activity towards azole-resistant strains. This finding is very interesting since the target of 2a is primarily the same as that of fluconazole, emphasizing the role played by the organometallic moiety. In vivo experiments conducted with 2a at a dose of 10 mg/Kg in mice model of Candida infections, while not decreasing fungal burden in the kidney, reduced distal distribution to liver and brain and greatly improved the inflammatory pathology in the kidney and colon, compared to untreated mice.