Purpose: Here, we aim to evaluate the antileishmanial activity of compounds with a benzoxazinoid (BX) skeleton, previously synthesized by our group, against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum promastigotes. Methods: Anti-promastigote activity, as well as cytotoxicity, were determined using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) colorimetric assays. The selectivity index (SI) for each compound was calculated using a ratio of the cytotoxicity of compounds and the geometric mean (GM) of antileishmanial concentrations to each species tested. The comparisons between groups were carried out using a t test or analysis of variance (one-way ANOVA). A P value of less than 0. 05 was considered significant. Results: All the compounds tested were active, with IC50 falling between 92 ± 6. 19 μ g/mL and 238± 6. 57 μ g/mL for L. braziliensis, and 89 ± 6. 43 μ g/mL and 188 ± 3. 58 μ g/mL against L. infantum. Bex2, Bex3, Pyr1, Pyr2, and Pyr4 were compounds that showed activity similar to the drug Glucantime® , exhibited low cytotoxicity against splenic hamster cells (CC50 raging between >400 and 105. 7± 2. 26 μ g/mL) and had favorable selectivity indices (SI 1. 12 to 3. 96). Conclusion: The analogs in question are promising prototypes for the pharmaceutical development of novel, safer and more effective leishmanicidal agents.