Piplartine is an alkamide found in different Piper species and possesses several biological activities, including antiparasitic properties. Thus, the aim of the present study was to evaluate a series of 32 synthetic piplartine analogues against the Leishmania amazonensis promastigote forms and establish the structure-activity relationship and 3D-QSAR of these compounds. The antileishmanial effect of the compounds was determined using the MTTmethod. Most compounds were found to be active against L. amazonensis. Among 32 assayed derivatives, compound (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity (IC50 = 0.007 ± 0.008 μM, SI > 10), followed by benzyl 3,4,5-trimethoxybenzoate (IC50 = 0.025 ± 0.009 μM, SI > 3.205) and (E)-furfuryl 3-(3,4,5-trimethoxyphenyl)-acrylate (IC50 = 0.029 ± 0.007 μM, SI > 2.688). It was found that the rigid substituents contribute to increasing antiparasitic activity against L. amazonensis promastigotes. The presence of the unsaturated heterocyclic substituent in the phenylpropanoid chemical structure (furfuryl group) resulted in a bioactive derivative. Molecular simplification of benzyl 3,4,5- trimethoxybenzoate by omitting the spacer group contributed to the bioactivity of this compound. Furthermore, bornyl radical appears to be important for antileishmanial activity, since (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity. These results show that some derivatives studied would be useful as prototype molecules for the planning of new derivatives with profile of antileishmanial drugs.