9Th Brazilian Symposium on Medicinal Chemistry

A series of 23 isoxazole analogues to nifurtimox was synthesized through 1,3-dipolar cycloaddition reaction between nitrofuran chloro-oxime and terminal acetylenes with different substitution pattern1 and obtained in moderate to good yields (45 – 91%). In vitro activity of isoxazole derivatives against amastigote form of Trypanosoma cruzi and cytotoxicity on LLC-MK2 mammalian cell was evaluated. Nine compounds were most active than benznidazole used as reference drug. In particular, the isoxazole derivative aryl substituted with SCH3 was found to be the most potent (IC50 = 0.33 μM) with high selectivity (SI = 67.63). This finding is very interesting, since compounds with SI > 10 are currently selected for in vivo studies. Moreover, this compound at concentration of 1 µM was able to kill 90% of parasites in vitro. In conclusion, good activity and low cytotoxicity of these compounds make them interesting candidates for in vivo studies against T. cruzi.