In the present work, the MeOH extract from stem barks of Calophyllum brasiliense Cambess. (Clusiaceae) displayed activity against amastigote forms of Trypanosoma cruzi and Leishmania infantum and was subjected to a bioactivity-guided fractionation to give two related coumarins - calanolides E1 (1) and E2 (2). Compounds 1 and 2 were actives to T. cruzi with EC₅₀ values of 12.1 and 8.2 μM, respectively. When tested against L. infantum, the EC₅₀ values were 37.1 and 29.1 μM, respectively. Compound 2, corresponding to anti isomer, showed the best selectivity index (SI) with values >24.4 to T. cruzi and >6.9 to L. infantum in comparison to the syn isomer 1. Furthermore, using an in silico multi-parametric prediction, both compounds did not contain any PAINS sub-structures. Therefore, these data suggest that coumarins 1 and 2 may contribute as scaffolds for the design of novel drug candidates for leishmaniasis and Chagas disease.