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.

Keywords: Caenorhabditis elegans larvae; Candida sp.; Cryptococcus neoformans; Histoplasma capsulatum; Paracoccidioides brasiliensis; Trichophyton mentagrophytes; Trichophyton rubrum; antifungal activity; broad-spectrum antifungal; nitrofuran derivates.

Figure 1

The nitrofuran derivatives, 1–17, as studied in this work.

Scheme 1

Reagents and conditions: (a) CDI, 1,4-dioxane; (b) RNH₂.

Scheme 2

Reagents and conditions: (a) H₂SO₄, CH₃COOH, 100 °C, 24 h.

Figure 2

Representative graphs of the MIC₉₀ obtained for each fungal species, for the 17 tested nitrofuran derivatives.

Figure 3

Caenorhabtis elegans larvae viability after treatment with the tested compounds. The larvae viability was greater than 80% with all the tested nitrofurans, even at the highest concentration of the compounds (250 µg/mL). The effects of the compounds were compared to the control group. Nitrofurans 1 and 12 showed no statistical difference with the control group in any concentration. On the other hand, compounds 3, 5 and 11, at the concentration of 250 µg/mL, showed statistical difference with the control group, with * p < 0.01, ** p < 0.05 and *** p < 0.001, respectively. Compound 5 also showed statistical difference with the control group at the concentrations of 125 µg/mL (p < 0.05) and 62.5 µg/mL (p < 0.001).

Figure 4

Images of L4 stage Caenorhabtis elegans: 32 larvae at a compound concentration equal to 250 µg/mL. (A)—control group, the black arrow indicates a live larva, in its sinusoidal form; (B–F)—representative images of compounds 1, 3, 5, 11, and 12, respectively; the black arrows point to a live larva in its characteristic shape (sinusoidal) and the orange arrow shows a dead larva in its characteristic rod shape.