Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages

Grecco, Simone dos Santos; Costa-Silva, Thaís A.; Jerz, Gerold; Sousa, Fernanda S. de; Londero, Vinicius S.; Galuppo, Mariana K.; Lima, Marta Lopes; Neves, Bruno J.; Andrade, Carolina Horta; Tempone, André G.; Lago, João Henrique G.

doi:10.1016/j.cbi.2017.08.017

Cited by 24 publications

(33 citation statements)

References 37 publications

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“…The pattern related to a tetrasubstituted aromatic ring confirmed the C-C linkage between two aromatic rings. The spectroscopic data of 1 – 6 were in accordance with those previously reported in the literature [ 6 , 7 , 12 – 18 ], allowing the identification of dehydrodieugenol B ( 1 ), 1-(8-propenyl)-3-[3′-methoxy-1′-(8-propenyl)phenoxy]-4,5-dimethoxybenzene ( 2 ), 1-[(7R)-hydroxy-8-propenyl]-3-[3′-methoxy-1′-(8′-propenyl)-phenoxy]-4-hydroxy-5-methoxybenzene ( 3 ), 1-[(7R)-hydroxy-8-propenyl]-3-[3′-methoxy-1′-(8′-propenyl)-phenoxy]-4,5-dimethoxybenzene ( 4 ), dihydrodieugenol ( 5 ), and dehydrodieugenol dimethyl ether ( 6 ) as shown in Fig. 2 .…”

Section: Resultssupporting

confidence: 89%

“…Previous studies by our group performed on the n -hexane extract from twigs of Nectandra leucantha (Lauraceae) yielded three neolignans with significant antileishmanial and immunomodulatory activity against Leishmania (L.) donovani [ 6 ]. Additionally, these related compounds displayed activity against Trypanosoma cruzi [ 7 ]. As part of our continuous studies of N. leucantha , in the present work, the crude n -hexane extract from twigs of this plant displayed activity against promastigote and amastigote forms of L. (L.) infantum (death rate of 100% at 300 μg/mL).…”

Section: Introductionmentioning

confidence: 99%

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Neolignans isolated from twigs of Nectandra leucantha Ness & Mart (Lauraceae) displayed in vitro antileishmanial activity

Grecco

Costa-Silva

Sousa

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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BackgroundThe therapeutic arsenal for the treatment of Leishmaniasis is limited and includes toxic compounds (antimonials, amphotericin B, pentamidine and miltefosine). Given these aspects, the search for new compounds based on floristic biodiversity is crucial. In the present work, we report the isolation, characterization and antileishmanial activity of six related neolignans (1–6) of bioactive extract from Nectandra leucantha (Lauraceae) twigs.MethodsDried and powdered twigs of N. leucantha were exhaustively extracted using n-hexane. The crude extract was dereplicated by HPLC/HRESIMS and subjected to column chromatography to yield pure compounds 1–6. Their chemical structures were identified via NMR and comparison of obtained data with those previously published in the literature. Biological assays of compounds 1–6 and their respective monomers (eugenol and methyleugenol) were performed using promastigote and amastigote forms of Leishmania (L.) infantum.ResultsDereplication procedures followed by chemical characterization of isolated compounds by NMR enabled the identification of related neolignans 1–6. Neolignans 2, 4 and 6 showed potential against amastigote forms of L. (L.) infantum (EC50 values of 57.9, 67.7 and 13.7 μM, respectively), while compounds 1 and 3 were inactive. As neolignans 2–4 are chemically related, it may be suggested that the presence of the methoxyl group at C4 constitutes an important structural aspect to increase antileishmanial potential against amastigote forms. Compound 6, which consists of a methylated derivative of compound 5 (inactive) showed antileishmanial activity similar to that of the standard drug miltefosine (EC50 = 16.9 μM) but with reduced toxicity (SI = 14.6 and 7.2, respectively). Finally, two related monomers, eugenol and methyleugenol, were also tested and did not display activity, suggesting that the formation of dimeric compounds by oxidative coupling is crucial for antiparasitic activity of dimeric compounds 2, 4 and 6.ConclusionThis study highlights compound 6 against L. (L.) infantum amastigotes as a scaffold for future design of new compounds for drug treatment of visceral leishmaniasis.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Neolignans isolated from twigs of Nectandra leucantha Ness & Mart (Lauraceae) displayed in vitro antileishmanial activity

Grecco

Costa-Silva

Sousa

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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“…Unlike mammalian cells, trypanosomatids present single mitochondria that are essential for survival, making this organelle a target for new chemotherapeutics 19 . In previous research, neolignans eupomatenoid-5 20 and 1-[(7 S )-hydroxy-8-propenyl]-3-[3′-methoxy-1′-(8′-propenyl)-phenoxy]-4,5-methoxybenzene 8 were found to induce depolarization of the mitochondrial membrane in L . ( L .)…”

Section: Discussionmentioning

confidence: 91%

“…The plasma membrane regulates the transport of nutrients, ions and pH homeostasis; due to its differential chemical composition and its essential role in parasite survival, the study of plasma membrane effects becomes indispensable when investigating new hits 3 . In previous studies, plasma membrane permeabilization was verified in Trypanosoma cruzi parasites treated with other neolignans such as dihydrodieugenol B 8 and 1-[(7S)-hydroxy-8-propenyl]-3-[3′-methoxy-1′-(8′-propenyl)-phenoxy]-4,5-methoxybenzene 7 . In the present work, the transmission electron microscopy data demonstrated no alteration of the L .…”

Section: Discussionmentioning

confidence: 95%

“…1) was the most selective, and also presented a promising immunomodulatory effect for visceral leishmaniasis. Recently, 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 . In continuation of this work, we here report the preparation and biological evaluation of four new semi-synthetic derivatives ( 1 – 4 ) of dehydrodieugenol B and methyl dehydrodieugenol B.…”

Section: Introductionmentioning

confidence: 99%

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

Amaral

Sousa

Silva

et al. 2019

Sci Rep

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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 . IC 50 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 Ca 2+ , 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.

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In Vitro and In Silico Evaluation of the Leishmanicidal and Trypanocidal Activities of Lignan Methylpiperitol Isolated from Persea Fulva

Alves Reis,

da Silva,

de Mattos Oliveira

et al. 2024

Chemistry & Biodiversity

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Neglected Tropical Diseases are a significant concern as they encompass various infections caused by pathogens prevalent in tropical regions. The limited and often highly toxic treatment options for these diseases necessitate the exploration of new therapeutic candidates. In the present study, the lignan methylpiperitol was isolated after several chromatographic steps from Persea fulva L. E. Koop (Lauraceae) and its leishmanicidal and trypanocidal activities were evaluated using in vitro and in silico approaches. The chemical structure of methylpiperitol was defined by NMR and MS spectral data analysis. The antiprotozoal activity of methylpiperitol was determined in vitro and indicated potency against trypomastigote forms of Trypanosoma cruzi (EC50 of 4.5±1.1 mM) and amastigote forms of Leishmania infantum (EC50 of 4.1±0.5 mM), with no mammalian cytotoxicity against NCTC cells (CC50>200 mM). Molecular docking studies were conducted using six T. cruzi and four Leishmania. The results indicate that for the molecular target hypoxanthine phosphoribosyl transferase in T. cruzi and piteridine reductase 1 of L. infatum, the methylpiperitol obtained better results than the crystallographic ligand. Therefore, the lignan methylpiperitol, isolated from P. fulva holds potential for the development of new prototypes for the treatment of Neglected Tropical Diseases, especially leishmaniasis.

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Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages

Cited by 24 publications

References 37 publications

Neolignans isolated from twigs of Nectandra leucantha Ness & Mart (Lauraceae) displayed in vitro antileishmanial activity

Neolignans isolated from twigs of Nectandra leucantha Ness & Mart (Lauraceae) displayed in vitro antileishmanial activity

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

In Vitro and In Silico Evaluation of the Leishmanicidal and Trypanocidal Activities of Lignan Methylpiperitol Isolated from Persea Fulva

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