Piplartine Synthetic Analogs: In Silico Analysis and Antiparasitic Study against Trypanosoma cruzi

Neglected tropical diseases (NTDs) cause thousands of deaths each year. Among these diseases, we find Chagas disease, whose etiologic agent is Trypanosoma cruzi. Piplartine is an alkamide present in various species of the genus Piper that possess trypanocidal activity. In this study, the antiparasitic potential of a collection of 23 synthetic analogs of piplartine against Trypanosoma cruzi 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 T. cruzi, showing IC50 values ranging from 2.21 to 35.30 mu M, 4.06 to 34.30 mu M, and 1.72 to 5.72 mu M, respectively. N-iso-butyl-3,4,5-trimethoxybenzamide (17) presented potent trypanocidal activity with an IC50 = 2.21 mu M 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 17 in T. cruzi.