Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as analogues of natural lignans with antiparasitic activity

Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural Lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against Trypanosoma cruzi amastigotes. Thirty-seven compounds were active, and eight of them had GI₅₀ values lower than 100 μM (GI₅₀ 88.4-12.2 μM). A qualitative structure activity relationship study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compounds. Compound 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole (31) was the most active in the series (GI₅₀ 12.2 μM), showing, in vitro, low toxicity and potency similar to benznidazole (GI₅₀ 10.2 μM). These results suggest that this compound can be a promising scaffold for the design of new trypanocidal compounds.

Anti-trypanosomatid agents; Isoxazole; Leishmania amazonensis; Triazole; Trypanosoma cruzi.