Organoselenium Has a Potent Fungicidal Effect on Cryptococcus neoformans and Inhibits the Virulence Factors.

Cryptococcosis therapy is often limited by toxicity problems, antifungal tolerance, and high costs. Studies approaching chalcogen compounds, especially those containing selenium, have shown promising antifungal activity against pathogenic species. This work aimed to evaluate the in vitro and in vivo antifungal potential of organoselenium compounds against Cryptococcus neoformans. The lead compound LQA_78 had an inhibitory effect on C. neoformans planktonic cells and dispersed cells from mature biofilms at similar concentrations. The fungal growth inhibition led to an increase in budding cells arrested in the G2/M phase, but the compound did not significantly affect structural cell wall components or chitinase activity, an enzyme that regulates the dynamics of the cell wall. The compound also inhibited titan cell (Tc) and enlarged capsule yeast (NcC) growth and reduced the body diameter and capsule thickness associated with increased capsular permeability of both virulent morphotypes. LQA_78 also reduced fungal melanization through laccase activity inhibition. The fungicidal activity was observed at higher concentrations (16 to 64 µg/mL) and may be associated with augmented plasma membrane permeability, ROS production, and loss of mitochondrial membrane potential. While LQA_78 is a nonhemolytic compound, its cytotoxic effects were cell type dependent, exhibiting no toxicity on Galleria mellonella larvae at a dose ≤46.5 mg/kg. LQA_78 treatment of larvae infected with C. neoformans effectively reduced the fungal burden and inhibited virulent morphotype formation. To conclude, LQA_78 displays fungicidal action and inhibits virulence factors of C. neoformans. Our results highlight the potential use of LQA_78 as a lead molecule for developing novel pharmaceuticals for treating cryptococcosis.

3-Alkenyltyrosines accessed by Suzuki-Miyaura coupling: a key intermediate in the synthesis and mechanistic study of povarov multicomponent reactions

3-Vinyl and 3-stilbenyl tyrosine derivatives, accessed by the Suzuki-Miyaura coupling reaction in good yields, are presented. These synthetic olefins then provided a fast and effective synthesis of functionalized quinolines by a silver-catalyzed, microwave-mediated Povarov reaction in just 40min. In addition, we demonstrate a tandem one-pot microwave-mediated Povarov-CuAAC (copper-catalyzed azide-alkyne cycloaddition) synthesis to provide a 1,2,3-triazole ring with 35% overall yield. We propose a Povarov/aromatization mechanism, based on high-resolution mass spectrometry experiments, combined with computational studies based on density functional theory (DFT) methods.