Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neo- lignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 mM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 mM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 mM. The phenolic ac- etate derivative of natural dehydrodieugenol