Synthesis and Antifungal Activity of Fmoc-Protected 1,2,4-Triazolyl-α-Amino Acids and Their Dipeptides Against Aspergillus Species
Authors: Sargsyan Tatevik , Stepanyan Lala , Panosyan Henrik , Hakobyan Hegine , Israyelyan Monika , Tsaturyan Avetis , Hovhannisyan Nelli , Vicidomini Caterina , Mkrtchyan Anna , Saghyan Ashot , Roviello Giovanni 
Published: December 2024

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. Aspergillus species, notably Aspergillus flavus and Aspergillus versicolor, are opportunistic pathogens that pose a threat to both animals and humans. In cattle, Aspergillus infections can lead to mycotic abortion, primarily in late pregnancy, and cause respiratory and gastrointestinal issues. As the incidence of such infections rises, effective antifungal therapies are needed, particularly in the face of increasing antifungal resistance. This study focuses on the synthesis and antifungal evaluation of novel Fmoc-protected 1,2,4-triazolyl-&alpha;-amino acids (5 and 6) and their dipeptides (8 and 9), designed to combat fungal pathogens with a targeted and po-tentially safer profile compared to traditional antifungal agents like fluconazole. Through opti-mized precipitation techniques and the activated ester method, we synthesized the compounds and evaluated their antifungal activity against Aspergillus versicolor (ATCC 12134) and Aspergillus flavus (ATCC 10567). The results showed that dipeptide (8) demonstrated promising antifungal activity at 0.16 mL, comparable to fluconazole, a standard treatment for fungal infections. Notably, increasing the concentration of fluconazole to 0.33 mL did not improve its antifungal efficacy, while the dipeptide's effect was enhanced with increased dosage, suggesting the potential of these dipeptides as more potent or selective antifungal agents. In contrast, the protected amino acid (5) exhibited consistent inhibition across all tested concentrations, aligning with the effects observed for fluconazole at higher concentrations. The increasing prevalence of fungal infections in im-munocompromised animals, coupled with the limited number of effective antifungal drugs, underscores the need for innovative therapeutic approaches. In cattle, Aspergillus infections can have devastating consequences for both animal health and agricultural productivity, with affected herds experiencing reduced milk production, poor fertility, and in severe cases, abortion. As conventional antifungal treatments may pose risks of resistance development or adverse side effects, novel antifungal peptides, such as the synthesized dipeptides in this study, present a promising alternative. These compounds offer the dual benefits of high bioactivity against pathogens like Aspergillus species and the potential for reduced resistance due to their distinct mechanisms of action. Our findings indicate that the synthesized 1,2,4-triazolyl dipeptides (8 and 9) hold significant promise as potential antifungal agents, not only for veterinary use in treating Aspergillus-induced diseases in cattle but also for broader applications in human and animal health. Given the rising concerns of antifungal resistance, these peptides, with their unique bio-active structures, could serve as a novel class of therapeutic agents with enhanced specificity and fewer side effects. Further research into their mechanism of action, in vivo efficacy, and safety profiles is warranted to fully realize their potential as antifungal drugs in clinical and agricultural settings.