Design, Synthesis, and In Vitro Evaluation of the Leishmanicidal Activity of New Aromatic Symmetrical...

A second generation of symmetrical 1,4-disubstituted 1,2,3-triazoles containing aromatic moieties was designed and synthesized from 2-hydroxy-1,3-bisazido-propane and terminal alkynes by copper-(I)-catalyzed alkyne-azide cycloaddition (CuAAC) as potential inhibitors of protein CYP51. The symmetrical bistriazoles (SBs) were obtained in moderate to excellent yields (49 to 95%). All synthetic nonsymmetric triazoles and the symmetric bistriazole derivatives were in vitro screened for the extracellular promastigote forms of Leishmania amazonensis. From this investigation, it emerged that symmetric bistriazole 12c (IC₅₀ = 19.24 μM) showed the highest potency against the flagellate form of the parasite followed by compounds 12b (IC₅₀ = 34.46 μM), 10 (IC₅₀ = 44.13 μM), and 4 (IC₅₀ = 42.81 μM). The cytotoxicity evaluation revealed that the most active compounds were also significantly toxic with SI ∼2, except for compounds 4 and 10 that showed SI values of 7.51 and 8.69, respectively. Considering SI > 8 as a selection criterion, only the diketone-bistriazole derivative 10 was submitted to further evaluation against the intracellular amastigote form, showing a significant cytotoxic effect, with an IC₅₀ value of 68.38 μM (SI = 5.61). To evaluate its potential toxicity on normal human cells, the most promising compound 10 was also assayed against human fibroblasts culture, showing a significantly smaller cytotoxicity (CC₅₀ = 568.09 μM, SI = 8.3) in comparison to amphotericin B (CC₅₀ = 22.95 μM, SI = 12.07). An in silico investigation showed that the most promising compound 10 bound inside the active pocket from the protein CYP51 with a binding energy of -9.96 kcal/mol.