Design, Synthesis, and In Vitro Evaluation of the Leishmanicidal Activity of New Aromatic Symmetrical 1,4-Disubstituted 1,2,3-Bistriazoles.

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 . From this investigation, it emerged that symmetric bistriazole 12c (IC = 19.24 μM) showed the highest potency against the flagellate form of the parasite followed by compounds 12b (IC = 34.46 μM), 10 (IC = 44.13 μM), and 4 (IC = 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 IC 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 (CC = 568.09 μM, SI = 8.3) in comparison to amphotericin B (CC = 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.