A semi-synthetic neolignan derivative from dihydrodieugenol B selectively affects the bioenergetic system of Leishmania infantum and inhibits cell division

Maiara Amaral,Fernanda S De Sousa,Andre G Tempone,Edward A Anderson,Thais A Costa Silva,Noemi N Taniwaki,Andrés Jimenez G Junior,João Henrique G Lago,Deidre M Johns

doi:10.1038/s41598-019-42273-z

Abstract

Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. Plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha, and their effects against intracellular amastigotes of Leishmania (L.) infantum evaluated in vitro. IC50 values between 6 and 35 µM were observed and in silico predictions suggested good oral bioavailability, no PAINS similarities, and ADMET risks typical of lipophilic compounds. The most selective (SI > 32) compound was chosen for lethal action and immunomodulatory studies. This compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca2+, possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania, inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies.

Highlights

Leishmaniasis, a neglected tropical disease caused by protozoan parasites of the Leishmania genus, affects more than 12 million people worldwide
Www.nature.com/scientificreports search for such natural leads against visceral leishmaniasis (VL), we previously described the anti-L. (L.) donovani activity of neolignans isolated from Nectandra leucantha Nees & Mart[6]
The activity was evaluated using the MTT method and the results showed that all four compounds killed 100% of the parasites at the highest concentration

Summary

Introduction

Leishmaniasis, a neglected tropical disease caused by protozoan parasites of the Leishmania genus, affects more than 12 million people worldwide. This disease is present in 98 countries and it is estimated that 60,000 new cases occur every year in Latin America alone[1]. The search for new drugs remains a necessity, especially for developing countries In this context, natural products are excellent prototypes for the synthesis of potent antiparasitic derivatives[3,4], and around 50% of all FDA-approved drugs are based in some form on natural product scaffolds[5]. We described the anti-Trypanosoma cruzi activity of dehydrodieugenol B and its natural methylated derivative, and an in silico analysis revealed a promising safety profile for these compounds[7,8]. Insight into the mechanism of lethal action of the most potent compound 2 was obtained using spectrofluorimetric assays, flow cytometry, and transmission electron microscopy, and its immunomodulatory potential in macrophages was investigated

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Conclusion