Synthesis and Antifungal Activity of Fmoc-Protected 1,2,4-Triazolyl-α-Amino Acids and Their Dipeptides Against <i>Aspergillus</i> Species
In recent years, fungal infections have emerged as a significant health concern across veterinary species, especially in livestock such as cattle, where fungal diseases can result in considerable economic losses, as well as in humans. In particular, <i>Aspergillus</i> species, notably &l...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
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| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/1/61 |
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| Summary: | In recent years, fungal infections have emerged as a significant health concern across veterinary species, especially in livestock such as cattle, where fungal diseases can result in considerable economic losses, as well as in humans. In particular, <i>Aspergillus</i> species, notably <i>Aspergillus flavus</i> and <i>Aspergillus versicolor</i>, are opportunistic pathogens that pose a threat to both animals and humans. This study focuses on the synthesis and antifungal evaluation of novel 9-fluorenylmethoxycarbonyl (Fmoc)-protected 1,2,4-triazolyl-α-amino acids and their dipeptides, designed to combat fungal pathogens. More in detail, we evaluated their antifungal activity against various species, including <i>Aspergillus versicolor</i> (ATCC 12134) and <i>Aspergillus flavus</i> (ATCC 10567). The results indicated that dipeptide <b>7a</b> exhibited promising antifungal activity against <i>Aspergillus versicolor</i> with an IC<sub>50</sub> value of 169.94 µM, demonstrating greater potency than fluconazole, a standard treatment for fungal infections, which showed an IC<sub>50</sub> of 254.01 µM. Notably, dipeptide <b>7a</b> showed slightly enhanced antifungal efficacy compared to fluconazole also in <i>Aspergillus flavus</i> (IC<sub>50</sub> 176.69 µM vs. 184.64 µM), suggesting that this dipeptide might be more potent even against this strain. Remarkably, <b>3a</b> and <b>7a</b> are also more potent than fluconazole against <i>A. candidus</i> 10711. On the other hand, the protected amino acid <b>3a</b> demonstrated consistent inhibition across all tested <i>Aspergillus</i> strains, but with an IC<sub>50</sub> value of 267.86 µM for <i>Aspergillus flavus</i>, it was less potent than fluconazole (IC<sub>50</sub> 184.64 µM), still showing some potential as a good antifungal molecule. Overall, our findings indicate that the synthesized 1,2,4-triazolyl derivatives <b>3a</b> and <b>7a</b> hold significant promise as potential antifungal agents in treating <i>Aspergillus</i>-induced diseases in cattle, as well as for broader applications in human health. Our mechanistic studies based on molecular docking revealed that compounds <b>3a</b> and <b>7a</b> bind to the same region of the sterol 14-α demethylase as fluconazole. Given the rising concerns about antifungal resistance, these amino acid derivatives, with their unique bioactive structures, could serve as a novel class of therapeutic agents. Further research into their in vivo efficacy and safety profiles is warranted to fully realize their potential as antifungal drugs in clinical and agricultural settings. |
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| ISSN: | 2218-273X |