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Neglected tropical diseases (NTDs) cause thousands of deaths each year. Among these diseases, we find Chagas disease, whose etiologic agent is <i>Trypanosoma cruzi.</i> Piplartine is an alkamide present in various species of the genus <i>Piper</i> that possess trypanocidal activity. In this study, the antiparasitic potential of a collection of 23 synthetic analogs of piplartine against <i>Trypanosoma cruzi</i> was evaluated in vitro. The compounds were prepared via amidation and esterification reactions using 3,4,5-trimethoxybenzoic acid as starting material. The products were structurally characterized using ¹H and ¹³C nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry. Of the twenty-three compounds tested in the cytotoxic activity assays, five presented good activity in the trypomastigote, epimastigote, and amastigote forms of <i>T. cruzi,</i> showing IC₅₀ values ranging from 2.21 to 35.30 µM, 4.06 to 34.30 µM, and 1.72 to 5.72 µM, respectively. <i>N-iso-</i>butyl-3,4,5-trimethoxybenzamide (<b>17</b>) presented potent trypanocidal activity with an IC₅₀ = 2.21 µM and selectively caused apoptosis (SI = 298.6). Molecular modeling experiments suggested the inhibitions of the histone deacetylase (HDAC) enzyme as the main trypanocidal mechanism of action of compound <b>17</b> in <i>T. cruzi</i>.