Synthesis and Evaluation of the Antifungal and Toxicological Activity of Nitrofuran Derivatives

Abstract

Fungal diseases affect more than 1 billion people worldwide. The constant global changes, the advent of new pandemics, and chronic diseases favor the diffusion of fungal pathogens such as Candida, Cryptococcus, Aspergillus, Trichophyton, Histoplasma capsulatum, and Paracoccidioides brasiliensis. In this work, a series of nitrofuran derivatives were synthesized and tested against different fungal species; most of them showed inhibitory activity, fungicide, and fungistatic profile. The minimal inhibitory concentration (MIC90) values for the most potent compounds range from 0.48 µg/mL against H. capsulatum (compound 11) and P. brasiliensis (compounds 3 and 9) to 0.98 µg/mL against Trichophyton rubrum and T. mentagrophytes (compounds 8, 9, 12, 13 and 8, 12, 13, respectively), and 3.9 µg/mL against Candida and Cryptococcus neoformans strains (compounds 1 and 5, respectively). In addition, all compounds showed low toxicity when tested in vitro on lung cell lines (A549 and MRC-5) and in vivo in Caenorhabditis elegans larvae. Many of them showed high selectivity index values. Thus, these studied nitrofuran derivatives proved to be potent against different fungal species, characterized by low toxicity and high selectivity; for these reasons, they may become promising compounds for the treatment of mycoses.

Evaluation of the Anti-Histoplasma capsulatum Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures

“…The nitrofuran derivatives 1 – 17 [ 28 ], as well as the indole compounds 18 – 48 , 50 – 54 [ 25 ], and 49 [ 32 ], were synthesized according to literature, and all the analytical data were in accordance with those reported previously.…”

“…In the scope of pharmacological replacement, additional activities of nitrofurans were discovered, such as antiparasitic and anti-proliferative agents [ 21 , 22 , 23 ]. Recently, some nitrofurans showed low toxicity when tested on human cell lines and potent antifungal and anti-biofilm activity against Candida species [ 24 , 25 ], with a capacity to inhibit cell adhesion and aggregation [ 26 , 27 , 28 ].…”

“…In light of previous discussions, we re-synthesized a series of nitrofuran ( Figure 1 ) and indole ( Figure 2 ) derivatives selected from our laboratory library [ 25 , 28 , 32 ], with the aim of identifying new anti- Histoplasma agents with low toxicity towards human cells.…”