*Article* **(***E***)-Piplartine Isolated from** *Piper pseudoarboreum***, a Lead Compound against** *Leishmaniasis*

**Juan C. Ticona 1,2,**†**, Pablo Bilbao-Ramos 3,4,**†**, Ninoska Flores 2, M. Auxiliadora Dea-Ayuela 3,5, Francisco Bolás-Fernández 3, Ignacio A. Jiménez 1,\* and Isabel L. Bazzocchi 1,\***


Received: 30 July 2020; Accepted: 3 September 2020; Published: 7 September 2020

**Abstract:** The current therapies of leishmaniasis, the second most widespread neglected tropical disease, have limited effectiveness and toxic side effects. In this regard, natural products play an important role in overcoming the current need for new leishmanicidal agents. The present study reports a bioassay-guided fractionation of the ethanolic extract of leaves of *Piper pseudoarboreum* against four species of *Leishmania* spp. promastigote forms, which afforded six known alkamides (**1**–**6**). Their structures were established on the basis of spectroscopic and spectrometric analysis. Compounds **2** and **3** were identified as the most promising ones, displaying higher potency against *Leishmania* spp. promastigotes (IC50 values ranging from 1.6 to 3.8 μM) and amastigotes of *L. amazonensis* (IC50 values ranging from 8.2 to 9.1 μM) than the reference drug, miltefosine. The efficacy of (*E*)-piplartine (**3**) against *L. amazonensis* infection in an in vivo model for cutaneous leishmaniasis was evidenced by a significant reduction of the lesion size footpad and spleen parasite burden, similar to those of glucantime used as the reference drug. This study reinforces the therapeutic potential of (*E*)-piplartine as a promising lead compound against neglected infectious diseases caused by *Leishmania* parasites.

**Keywords:** *Piper pseudoarboreum*; bioassay-guided fractionation; leishmanicidal activity; alkamides; (*E*)-piplartine
