Cinnamic acids derived compounds with antileishmanial activity target Leishmania amazonensis arginase

Abstract

This study describes the activity of five natural hydroxycinnamic acids and derived compound: caffeic (1), rosmarinic (2), chlorogenic (3), and cryptochlorogenic (4), acids and isoverbascoside (5). All compounds inhibited Leishmania amazonensis arginase with IC -in range of 1.5-11 μM. Compounds 2 and 5 also showed activity against promastigotes of L. amazonensis with IC = 61 (28-133) μM and IC = 14 (9-24) μM, respectively. Further computational studies applying molecular docking simulations were performed on the competitive inhibitors to gain insight into the molecular basis for arginase inhibition and could be exploited to the development of new antileishmanials drug targeting parasite arginase.

Cinnamides Target Leishmania amazonensis Arginase Selectively

“…To gain insight into the binding modes of the competitive inhibitors (CAPA, 6, 13, 14, and 17) of L-ARG we performed an in silico investigation based on molecular docking coupled to the evaluation of ligand binding energy, as previously described [15,17,18]. Moreover, the significant differences, regarding the above mentioned inhibitors, in inhibiting L-ARG with respect to the mammalian arginase (bovine), prompted us to design a series of additional studies, in order to understand the different behavior of the compounds.…”

“…Protein preparation. According to our previous works [15,17,18] we used the crystallized structure of the L. mexicana arginase (PDB ID: 4IU1) [25], available in PDB, for the computational studies. This structure was imported into Maestro suite and submitted to the protein preparation wizard protocol implemented in Maestro suite 2016 (Protein Preparation Wizard workflow 2016) for obtaining a reasonable starting structure for further in silico experiments [34,39].…”

“…This technique was used on the docking complexes (L-ARG/inhibitors; B-ARG/inhibitors) presented in this study, and obtained by the molecular docking calculations. The software was employed to calculate the ligand binding energy (∆G bind ), as previously reported [15,17,18].…”

“…Caffeic acid and derived compounds, such as chlorogenic and rosmarinic acids, were previously described against L. amazonensis promastigotes and amastigotes [14]. These compounds were also described as good L. amazonensis arginase (L-ARG) inhibitors [15]. Previously, a series of nineteen cinnamide derivatives were designed, synthesized, and evaluated for their inhibitory activity against mammalian arginase.…”

Antileishmanial activity and ultrastructural changes of related tetrahydrofuran dineolignans isolated from Saururus cernuus L. (Saururaceae)

“…Leishmaniasis can be presented in four clinical forms, cutaneous, visceral, diffuse cutaneous and mucocutaneous, being cutaneous form is the most common among them all . In the last 5 years, cutaneous leishmaniasis has affected approximately 1 million people, while 300 000 cases have been estimated for visceral leishmaniasis . Leishmania amazonensis is the aetiologic agent of localized cutaneous leishmaniasis but some strains of this species can cause the most severe clinical form, the anergic diffuse leishmaniasis …”