In our search for new safe antiparasitic agents, an enzymatic pathway was applied to synthesize a series of <i>N</i>-pyridinylmethyl amides derived from structurally different carboxylic acids. Thirty derivatives, including 11 new compounds, were prepared through lipase-catalyzed acylation in excellent yields. In order to optimize the synthetic methodology, the impact of different reaction parameters was analyzed. Some compounds were evaluated as antiproliferative agents against <i>Trypanosoma cruzi</i>, the parasite responsible for American trypanosomiasis (Chagas' disease). Some of them showed significant activity as parasite proliferation inhibitors. Amides derived from 2-aminopicoline and stearic and elaidic acids were as potent as nifurtimox against the amastigote form of <i>T. cruzi</i>, the clinically relevant form of the parasite. Even more, a powerful synergism between nifurtimox and <i>N</i>-(pyridin-2-ylmethyl)stereamide was observed, almost completely inhibiting the proliferation of the parasite. Besides, the obtained compounds showed no toxicity in Vero cells, making them excellent potential candidates as lead drugs.