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Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of <i>Leishmania amazonensis</i>, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered <b>18</b> and <b>22</b> were chosen for additional studies. Both <b>18</b> and <b>22</b> were active (GI₅₀ ≤ 2 µM, cytotoxic CC₅₀ > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that <b>18</b> significantly depolarized the plasma membrane potential (<i>p</i> < 0.05) and the mitochondrial membrane potential (<i>p</i> < 0.05) when compared to untreated cells. Although neither <b>18</b> nor <b>22</b> induced nitric oxide production in infected macrophages, <b>18</b> induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds <b>18</b> and <b>22</b> could be used as tools for designing new chemotherapies against leishmaniasis.