Drug repurposing-inspired design of miconazole-based 1,2,3-triazoles as antichagasic agents

Drug-repurposing strategies have been widely explored to accelerate the development of new treatments for Chagas disease, leveraging compounds with previously established safety profiles. Among these, azole antifungals have attracted attention due to their inhibitory activity against 14-α-lanosterol demethylase (CYP51), an enzyme also present in Trypanosoma cruzi and essential for its ergosterol biosynthesis. Inhibition of this pathway compromises parasite membrane integrity and function and several azoles, including posaconazole, ravuconazole, and miconazole, have demonstrated significant in vitro trypanocidal activity. In this work, we have synthesized new 1,2,3-triazoles as miconazole analogues using eugenol and its analogues as scaffolds. These compounds were initially evaluated against epimastigote forms of T. cruzi and a benzoyl eugenol-derived triazole 16 (IC₅₀ = 37.1 μM) shown trypanocidal potential close to benznidazole (IC₅₀ = 32.3 μM). This compound was further evaluated against trypomastigote and amastigote forms of T. cruzi, displaying IC₅₀ values of 1.4 μM and 2.9 μM, respectively, whereas benznidazole presented IC₅₀ values of 4.09 μM and 3.07 μM, with selectivity indexes of 110 and 53, respectively, considering healthy neonatal rat cardiomyoblast cell line (H9c2 cells). Docking studies suggested CYP51 as a putative molecular target, with compound 16 adopting a binding mode similar to known azole inhibitors. DFT calculations indicated weaker Fe-heme coordination for the 1,2,3-triazole moiety compared to classical azoles, suggesting that inhibition may depend on additional interactions within the binding site. Consistently, the compounds were inactive against Candida species. This finding suggests a degree of selectivity toward the target pathogens evaluated in this study, however additional investigations are required to confirm this selectivity profile. Given the known risk of human CYP inhibition associated with azole derivatives, this observation may be particularly relevant.